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[ CAS No. 22494-42-4 ] {[proInfo.proName]}

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Chemical Structure| 22494-42-4
Chemical Structure| 22494-42-4
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Product Details of [ 22494-42-4 ]

CAS No. :22494-42-4 MDL No. :MFCD00057834
Formula : C13H8F2O3 Boiling Point : -
Linear Structure Formula :HO2CC6H3(OH)C6H3F2 InChI Key :HUPFGZXOMWLGNK-UHFFFAOYSA-N
M.W : 250.20 Pubchem ID :3059
Synonyms :
MK-647;5-(2,4-Difluorophenyl)salicylic Acid;Dflunisal;Fluodonil;Fluniget;Flovacil;Dolobis;Dolobid
Chemical Name :2',4'-Difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylic acid

Calculated chemistry of [ 22494-42-4 ]

Physicochemical Properties

Num. heavy atoms : 18
Num. arom. heavy atoms : 12
Fraction Csp3 : 0.0
Num. rotatable bonds : 2
Num. H-bond acceptors : 5.0
Num. H-bond donors : 2.0
Molar Refractivity : 60.78
TPSA : 57.53 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -4.67 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.49
Log Po/w (XLOGP3) : 4.44
Log Po/w (WLOGP) : 3.88
Log Po/w (MLOGP) : 3.34
Log Po/w (SILICOS-IT) : 3.23
Consensus Log Po/w : 3.27

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -4.55
Solubility : 0.00706 mg/ml ; 0.0000282 mol/l
Class : Moderately soluble
Log S (Ali) : -5.37
Solubility : 0.00108 mg/ml ; 0.0000043 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -4.28
Solubility : 0.0132 mg/ml ; 0.0000528 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.96

Safety of [ 22494-42-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335-H351-H361 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 22494-42-4 ]

* 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.

  • Downstream synthetic route of [ 22494-42-4 ]

[ 22494-42-4 ] Synthesis Path-Downstream   1~93

  • 1
  • [ 22494-42-4 ]
  • [ 108-24-7 ]
  • [ 55543-97-0 ]
YieldReaction ConditionsOperation in experiment
80% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With pyridine In dichloromethane for 0.5h; Stage #2: acetic anhydride In dichloromethane at 20℃; for 3h; Synthesis of acetyldiflunisal The synthetic route of acetyldifunisal was shown in Fig. 1. The solution of diflunisal (0.5 g, 2 mmol) and pyridine (0.34 mL, 4 mmol) in CH2Cl2 (30 mL) was stirred for 30 min and then acetic anhydride (0.38 mL, 2 mmol) was added dropwise to the mixture by a syringe. The reaction mixture was stirred at room temperature for about 3 h until the starting material was disappeared by TLC. After the reaction completion, 1 M HCl was used to precipitate, filtrate, wash, and dry to afford acetyldiflunisal, which was purified by re-crystallization from CH2Cl2. Yield: 80%; m.p. 161-163 °C; HPLC analysis (gradient: MeOH-CH3CN-0.4% HOAC = 23:30:47, flow rate: 1.0 mL/min): tR = 16.7 min, Purity >99%. 1H NMR (500 MHz, CDCl3, δ/ppm): 2.40 (m, 3H, -COCH3), 7.45 (m, 1H, 6′-H), 6.98 (m, 2H, 3′, 5′-H), 7.78 (d, 1H, J = 8.4 Hz, 6-H), 7.23 (d, 1H, J = 8.4 Hz, 5-H), 8.26 (s, 1H, 2-H). 13C NMR (125 MHz, DMSO-d6, δ/ppm): 169.73 (COOH), 165.73 (CH3COO-), 162.47 (dd, J = 246.1, 12.4 Hz, C-4′), 159.56 (dd, J = 247.4, 12.3 Hz, C-2′), 150.24 (C-4), 134.45 (C-6), 132.50 (C-1), 132.43 (dd, J = 13.4, 7.0 Hz, C-6′), 131.98 (C-2), 124.79 (C-5), 124.73 (C-3), 123.68 (dd, J = 13.1, 3.5 Hz, C-1′), 112.73 (dd, J = 21.3, 3.0 Hz, C-5′), 105.10 (t, J = 26.3 Hz, C-3′), 21.32 (CH3COO-).
  • 2
  • [ 22494-42-4 ]
  • [ 64-31-3 ]
  • morphine diflunisal [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium hydroxide In ethanol; water for 1h; 115 5R,6S,9R,13S,14R-Morphine difunisalate may be prepared using the following synthetic scheme. Difunisal (0.2502 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. Morphine sulfate pentahydrate (0.3794 g, 0.50 mmol) is dissolved in a minimal volume of water and combined with the ethanolic difunisalate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4×90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight.
  • 4
  • [ 67-56-1 ]
  • [ 22494-42-4 ]
  • [ 55544-00-8 ]
YieldReaction ConditionsOperation in experiment
89% With sulfuric acid for 20h; Reflux; Inert atmosphere;
85% With sulfuric acid for 12h; Reflux; 1.1 H2SO4 (9.6 mL, 179.12 mmol) was added to a solution of diflunisal (15.0 g, 59.95 mmol) in MeOH (200 mL). The reaction mixture was refluxed for 12 h and it was allowed to reach r.t. Solids were collected by filtration and washed with cold MeOH (20 mL) to furnish 13.42 g of methyl 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylate (white solid, yield: 85%).1H NMR (CDCl3, 250 MHz) δ ppm: 10.84 (s, 1H), 7.98 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.36 (c, J1=8.8 Hz, J2=6.8 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 6.92 (m, 2H), 3.97 (s, 3H).
85% With sulfuric acid for 12h; Reflux; B-1.1 Step 1 : (Methyl 2,4'-difluoro-4-hydroxybiphenyl)-3-carboxylate Step 1 : (Methyl 2,4'-difluoro-4-hydroxybiphenyl)-3-carboxylate H2S04 (9.6 mL, 179.12 mmol) was added to a solution of diilunisal (15.0 g, 59.95 mmol) in MeOH (200 mL). The reaction mixture was refluxed for 12 h and it was allowed to reach r.t. Solids were collected by filtration and washed with cold MeOH (20 mL) to furnish 13.42 g of methyl 24'-difluoro-4-hydroxybiphenyl-3-earboxylate (white solid, yield: 85%). NMR (CDCI3, 250 MHz) δ ppm: 10.84 (s, 1H), 7.98 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.36 (c, J i = 8.8 Hz, J2 = 6.8 Hz, 1H), 7.06 (d, J= 8.8 Hz, 1H), 6.92 (m, 2H), 3.97 (s, 3H).
75% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane Schlenk technique; Inert atmosphere; Stage #2: methanol With ammonia In dichloromethane at 20℃; for 6.16667h; Cooling with ice;
65% With sulfuric acid for 3h; Heating;
With sulfuric acid Heating;
With sulfuric acid for 3h; Reflux;
With sulfuric acid
With sulfuric acid

Reference: [1]Bellotti, Peter; Glorius, Frank; Heidrich, Bastian; Huang, Huan-Ming; Pflüger, Philipp M.; Schwarz, J. Luca [Journal of the American Chemical Society, 2020, vol. 142, # 22, p. 10173 - 10183]
[2]Current Patent Assignee: GENMEDICA THERAPEUTICS SL.; GENMEDICA - US2012/149769, 2012, A1 Location in patent: Page/Page column 21
[3]Current Patent Assignee: GENMEDICA THERAPEUTICS SL. - WO2013/37985, 2013, A1 Location in patent: Page/Page column 79
[4]Yang, Yu; Borel, Timothy; De Azambuja, Francisco; Johnson, David; Sorrentino, Jacob P.; Udokwu, Chinedum; Davis, Ian; Liu, Aimin; Altman, Ryan A. [Journal of Medicinal Chemistry, 2021, vol. 64, # 1, p. 797 - 811]
[5]Kuecuekguezel, S. Gueniz; Mazi, Adil; Sahin, Fikrettin; Oeztuerk, Suzan; Stables, James [European Journal of Medicinal Chemistry, 2003, vol. 38, # 11-12, p. 1005 - 1014]
[6]Kuecuekguezel, S. Gueniz; Kuecuekguezel, Ilkay; Tatar, Esra; Rollas, Sevim; Sahin, Fikrettin; Guelluece, Medine; De Clercq, Erik; Kabasakal, Levent [European Journal of Medicinal Chemistry, 2007, vol. 42, # 7, p. 893 - 901]
[7]Aydin, Sevil; Kaushik-Basu, Neerja; Oezbas-Turan, Suna; Akbuga, Juelide; Tiber, Pinar Mega; Orun, Oya; Gurukumar; Basu, Amartya; Kuecuekguezel, S. Gueniz [Letters in drug design and discovery, 2014, vol. 11, # 2, p. 121 - 131]
[8]Senkardes, Sevil; Kaushik-Basu, Neerja; Durmaz, Irem; Manvar, Dinesh; Basu, Amartya; Atalay, Rengul; Guniz Kucukguzel [European Journal of Medicinal Chemistry, 2016, vol. 108, p. 301 - 308]
[9]Coşkun, Göknil Pelin; Djikic, Teodora; Hayal, Taha Bartu; Türkel, Nezaket; Yelekçi, Kemal; Şahin, Fikrettin; Küçükgüzel, Ş. Güniz [Molecules, 2018, vol. 23, # 8]
  • 5
  • [ 89-55-4 ]
  • [ 144025-03-6 ]
  • [ 22494-42-4 ]
YieldReaction ConditionsOperation in experiment
99% With 2-[5-(4-methylphenyl)isoxazol-3-yl]-5-(5-phenylisoxazol-3-yl)-1,3,4-oxadiazole·2PdCl2; potassium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 0.0166667h; General procedure: A 0.01 solution of L1-4·PdCl2 (0.2 mol % Pd) in DMF (0.1-0.2 ml)(or 0.8-4 mg of the respective Pd/Fe composite) was addedto a mixture of aryl(hetaryl)boronic acid (1.20 mmol), aryl-(hetaryl) bromide (1.00 mmol), Bu4NBr (3.2 mg, 0.01 mmol,used in the case of aryl halides that were insoluble in water),and K2CO3 (0.35 g, 2.5 mmol) in 2 (10 ml) (or in 10 mlof 1:1 methanol-water mixture). The reaction mixture wasvigorously stirred at the indicated temperature until fullconversion was obtained. The reaction progress wascontrolled by TLC method (eluent hexane-Et2O, 2:1). In thecase of activated aryl bromides, the reaction was veryexothermic, therefore it was important to use an effectivereflux condenser for larger scale syntheses. In the cases when the reaction products were aryl(hetaryl)benzoic acids, analytically pure samples were obtainedby diluting the reaction mixture with water, heating, filteringin order to remove an insignificant amount (~0.2 mol %) ofpalladium black and the homocoupling product, diluted with10-15% (v/v) of ethanol, heated to ~50C, and slowly,while stirring, acidified with 5% HCl to pH 2-3. Theprecipitate that formed after cooling was easily filtered, andpure compounds were isolated without a need forchromatographic separation. In the case when Pd/Fe wasused, the catalyst was separated after the completion of thereaction with the aid of an external magnet and the reactionmixture was used as described above. The recovered Pd/Fecatalyst could be used again after washing with water andacetone. In the case of biaryls (heterobiaryls) that wereinsoluble in water, the reaction mixture was diluted withsaturated NaCl solution, extracted with Et2O or EtOAc, theextract was dried over Na2SO4 and filtered through a thinsilica gel layer. The solvent was evaporated on a rotaryevaporator, and the residue, as a rule, had a purity of atleast 99%. Analytically pure samples were obtained by recrystallization of biaryls from a minimal amount ofaqueous alcohol (10-20% (v/v) 2) or by converting theamines to hydrochlorides. The residual palladium contentin the target products was in the range from 0.5 to 2.2 ppmaccording to the results of atomic absorption spectroscopy.
98.37% With potassium carbonate; palladium dichloride; In water; N,N-dimethyl-formamide; at 75℃;Sonication; Cooling; 120ml of distilled water,120ml of N,N-dimethylformamide mixed into the ultrasonic reactor and ultrasonically mixed to form solution A,Add 53.2 mg of PdCl2 (0.03 mmol) in a cold water bath and disperse evenly. Add 7.2 g of 2,4-difluorophenylboronic acid (45 mmol).6.51g 5-bromosalicylic acid (30 mmol) was dissolved and dispersed in a cold water bath.Finally, 3.36 g of K2CO3 (60 mmol) was added to dissolve and disperse.The reaction was carried out in an ultrasonic reactor at a temperature of 75 C and an ultrasonic power of 175 W for 100 min.After the reaction is completed, the liquid filtration catalyst after the reaction isTo the filtrate, a concentration of 1 mol/L of HCl was added and the mixture was shaken until the precipitated flocculent precipitate no longer disappeared, and 2000 ml of distilled water was added to the filtrate, and the mixture was allowed to stand.The flocculent precipitate of fluorophenylsalicylic acid was completely precipitated and filtered to obtain a white cake.The filter cake was dissolved in 200 ml of ethyl acetate, and washed with deionized water for 3 times.The upper organic phase was taken, dried over 45 g of anhydrous sodium sulfate, filtered over anhydrous sodium sulfate, and evaporated under vacuo to give a white solid.Recrystallization temperature 5 C, recrystallization time 10 h,Filtration to obtain a refined product of fluorophenylsalicylic acid,Product yield is 98.37%,The product purity is 99.89%.
97% With C11H8Cl4N2O3Pd; potassium carbonate; In methanol; water; N,N-dimethyl-formamide; at 100℃; for 0.0833333h; General procedure: To a mixture of 1.20 mmol of arylboronic acid, 1.00 mmol of aryl(hetaryl) bromide, 3.2 mg (0.01 mmol) of Bu4NBr (for water insoluble aryl halides) and 0.35 g (2.5 mmol) K2CO3 in 5 mL of H2O (or in 5 mL of equal volumes of water and methanol) pre-heated to 80C was added 0.1 mL of a suspension of L1-4PdCl2 complexes (0.1 mol % Pd) in methanol-DMF mixture (0.01 M). The reaction mixture was stirred vigorously at the same temperature (Table 4) to complete conversion. The reaction progress was monitored by TLC (eluent hexane-Et2O, 3 : 1). In the case of activated aryl bromides the reaction was highly exothermic that should be considered at the synthesis scaling. If the reaction products were aryl(hetaryl)benzoic acids, to obtain ananalytically pure sample the reaction mixture was diluted with water, heated, and filtered from mino ramounts (~ 0.1 mol %) of palladium black. Then about 10-15 vol % of alcohol was added, the mixture wa sheated to ~50C and acidified carefully with 10% HCl to adjusting pH = 2-3. As a result, the formed precipitate was filtered off and dried to provide analytically pure samples without the use of chromatographic methods. In the case of water-insoluble biaryls (heterobiaryls), the reaction mixture was diluted with a saturated solution of NaCl, extracted with Et2O or EtOAc, the extract was dried with Na2SO4 and filtered through a bed of silica gel. The solvent was removed to give the target compound with a purity ? 99% .Analytically pure sample was obtained by recrystallization from the minimum amount of aqueous alcohol (about 10-20 vol % of 2), or by conversion of amines to hydrochlorides.
90% With potassium carbonate; In water; at 20℃; for 6h;Green chemistry; General procedure: A 50 mL flask was charged with an aryl halide (1.0 mmol), anaryl boronic acid (1.2 mmol), K2CO3 (2.0 mmol), nanocatalyst(0.05 mol% Pd) and deionized water (5 mL). The reactionwas stirred at room temperature for 4 h. The progress ofthe reaction was monitored by thin-layer chromatography After the reaction was completed, distilled water (25 mL) wasadded to the mixture and dilute 2 mol/L HCl was added dropwiseto pH 3.0-4.0 with stirring, and the mixture was heatedto 100 C for 10 min. The white solid that had formed wasfiltered off and washed with hot water. After drying, it wasdissolved in ether (5 mL) and was rapidly separated using asilica gel column. Elution with ether left behind small amountsof impurities and traces of palladium black to give a crudeproduct. The ether solution was evaporated to 3-5 mL andrecrystallized to obtain a pure product. All the products 3a-uare known compounds and were characterized by comparingtheir melting points and 1H NMR spectra with those preparedrecently by using a water-soluble glycine-based Pd catalyst,PdCl2(NH2CH2CO2H)2.10 The melting points and 1H NMRdata of 3a-u are listed in the supplemental material.
86.97% With potassium carbonate; In N,N-dimethyl-formamide; at 150℃; for 4h; The 15mmol2,4-difluorophenyl boronic acid, 10mmol5- bromine salicylic acid, 0.1mmol o-phenylenediamine condensation of benzaldehyde bis Schiff base complexes of palladium catalyst, 20mmol of potassium carbonate were added to 80ml volume percentage of 50% of N, N - dimethylformamide an aqueous solution of, the reaction mixture was stirred at 150 240 minutes, the reaction was stopped, cooled to room temperature, the catalyst was recovered by filtration, to the filtrate was added 800ml of deionized water, boiled for 20 minutes, cooled to room temperature and mass fraction 37.5% of the HCl reaction mixture was adjusted to pH 3 and stirred to precipitate Diflunsial flocculent precipitate completely, filtration, distillation of the reaction solvent recovered in the filtrate, and the filter cake was added diethyl ether mass 5:1 the filter cake was dissolved, together with 50mL of deionized water three times to remove water-soluble impurities, to take the upper organic phase was dried over anhydrous sodium sulfate, anhydrous sodium sulfate was filtered off, the filtrate was evaporated to give the crude product Diflunsial, then in = 3/1 by volume ethanol - aqueous solution at 2 recrystallized from 12 hours to obtain Diflunsial products, by IR, 1 HNMR and HPLC analysis, the yield was Diflunsial to 86.97%.

  • 6
  • [ 21062-20-4 ]
  • [ 22494-42-4 ]
  • 6-bis[(2-carboxy-4(2',4'-difluorophenyl)phenyl)]glycolate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With pyridine In tetrahydrofuran at 20℃; for 0.5h; 5 To a solution of 10.50 g of diflunisal (0.042 mol.) and 3.7 mL of anhydrous pyridine (0.045 mol.) in 100 mL of anhydrous THF was added 3.42 g of diglycolyl chloride (0.02 mol.) in 25 mL of anhydrous THF 1 in a slow drop- wise fashion . A white precipitate was formed during the addition. The reaction mixture was stirred at ambient temperature for an additional 30 minutes. The reaction mixture was poured into 1 L of ice-water containing 5 mL of cone. HCl. After stirring for 15 minutes, the white precipitate was filtered and washed with water until the washings were neutral to pH paper. The product was dried overnight in a vacuum oven at 40 0C. After drying, the crude product was suspended in 100 mL of hexane/ethyl acetate (75:25, v/v) solvent mixture, stirred for 30 minutes, and filtered. The product was dried overnight in a vacuum oven at 40 0C. Isolated yield was H g. 1H NMR (CDCl3+DMSO-d6): 7.96 (d, 2H, J = 1.3 Hz), 7.48 (dd, 2H, J = 6.5 and 1.8 Hz), 7.26-7.02 (m, 2H), 7.0 (d, 2H, J = 8.2 Hz), 6.80-6.68 (m, 4H), 4.52 (bs, exchanged with D2O), 4.45 (s, 4H)
  • 7
  • [ 22494-42-4 ]
  • [ 14252-80-3 ]
  • bupivacaine diflunisal salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
With alkaly hydroxide or an strong acid solution; In water;pH 5 - 7;Acidic conditions; The compound in Example 1 was also prepared by dissolving an amount of <strong>[14252-80-3]<strong>[14252-80-3]bupivacaine</strong> hydrochloride</strong> in water. This solution was added to an aqueous solution (pH 8.0) containing an eqiumolar amount of diflunisal. After mixing the pH of the reaction mixture was adjusted to pH 5-7 by using a suitable alkali hydroxide or an strong acid solution. The precipitated salt was isolated and recrystallized as described in Examples 1and 2.
  • 8
  • [ 22494-42-4 ]
  • [ 14252-80-3 ]
  • bupivacaine diflunisal salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
In acetone; at 20℃; for 3h; <strong>[14252-80-3]Bupivacaine</strong> free base 0.5 g (1.73 mmol) was dissolved in 10 ml acetone and diflunisal (0.43 g, 1.73 mmol) dissolved in 10 ml acetone was added. The reaction solution was left for 3 hours at ambient temperature. Acetone was removed by evaporation in vacuo. The resulting solid was recrystallized from 80% aqueous 2-proponol yielding the bupivacaine-diflunisal salt crystalline salt in a satisfactory yield. Basic characteristics of the said salt are given in Section: " Materials and apparatus used in the examples".
  • 9
  • [ 22494-42-4 ]
  • [ 89365-50-4 ]
  • 4-hydroxy-alpha1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-5-(2,4-difluorophenyl)salicylic acid salt [ No CAS ]
  • 10
  • [ 22494-42-4 ]
  • [ 1867-66-9 ]
  • rac-ketamine difunisalate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium hydroxide In ethanol; water for 1h; 42 rac-Ketamine difunisalate may be prepared using the following synthetic scheme. Difunisal (0.2502 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. rac-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic difunisalate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4×90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight.
  • 11
  • [ 22494-42-4 ]
  • [ 29485-83-4 ]
  • 5R,6S,9R,13S,14R-codeine difunisalate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium hydroxide In ethanol; water for 1h; 100 5R,6S,9R,13S,14R-Codeine difunisalate may be prepared using the following synthetic scheme. Difunisal (0.2502 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. Codeine sulfate (0.3484 g, 0.50 mmol) is dissolved in a minimal volume of water and combined with the ethanolic difunisalate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4×90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight.
  • 12
  • [ 22494-42-4 ]
  • [ 1639-60-7 ]
  • d-propoxyphene difunisalate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium hydroxide In ethanol; water for 1h; 27 d-Propoxyphene difunisalate may be prepared using the following synthetic scheme. A solution of 5-(2,4-difluorophenyl)salicylic acid (herein referred to as difunisal) (0.2502 g, 1.00 mmol) is prepared in a minimal volume of ethanol and is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. d-Propoxyphene hydrochloride (0.3759 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic difunisalate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4×90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight.
  • 13
  • [ 22494-42-4 ]
  • [ 33643-47-9 ]
  • (S)-ketamine difunisalate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium hydroxide In ethanol; water for 1h; 56 (S)-Ketamine difunisalate may be prepared using the following synthetic scheme. Difunisal (0.2502 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. (S)-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic difunisalate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4×90 mL). The organic layers are combined and the solvent removed by rotary evaporation.
  • 14
  • [ 22494-42-4 ]
  • [ 125-72-4 ]
  • levorphanol difunisalate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium hydroxide In ethanol; water for 1h; 130 Levorphanol difunisalate may be prepared using the following synthetic scheme. Difunisal (0.2502 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. Levorphanol tartrate dihydrate (0.4435 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic difunisalate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4×90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight.
  • 15
  • 5R,9R,13S,14R-hydrocodone bitartrate [ No CAS ]
  • [ 22494-42-4 ]
  • 5R,9R,13S,14R-hydrocodone difunisalate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium hydroxide In ethanol; water for 1h; 85 5R,9R,13S,14R-Hydrocodone difunisalate may be prepared using the following synthetic scheme. Difunisal (0.2502 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. 5R,9R,13S,14R-Hydrocodone bitartrate hemipentahydrate (0.4945 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic difunisalate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4×90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight.
  • 16
  • [ 22494-42-4 ]
  • [ 1095-90-5 ]
  • rac-methadone difunisalate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium hydroxide In ethanol; water for 1h; 70 rac-Methadone difunisalate may be prepared using the following synthetic scheme. Difunisal (0.2502 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. rac-Methadone hydrochloride (0.3459 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic difunisalate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4×90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight.
  • 17
  • [ 22494-42-4 ]
  • [ 124-90-3 ]
  • 5R,9R,13R,14S-oxycodone difunisalate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium hydroxide In ethanol; water for 1h; 145 5R,9R,13R,14S-Oxycodone difunisalate may be prepared using the following synthetic scheme. Difunisal (0.2502 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. Oxycodone hydrochloride (0.3518 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic difunisalate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4×90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight.
  • 18
  • [ 22494-42-4 ]
  • [ 459-73-4 ]
  • [ 850008-61-6 ]
YieldReaction ConditionsOperation in experiment
35% With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 20℃; 21.1 Example 21 Ethyl ester of N-[5-(2,4-difluorophenyl-3-iodo-salicyloyl]-glycine Step 1 - Preparation of the ethyl ester of N-[5-(2,4-difluorophenyl)salicyloyl]-glycine 500 mg (1.998 mmol) of diflunisal and 270 mg (1.99 mmol) of HOBt dissolved in the minimum quantity of dichloromethane were placed in a flask. 206 mg (1.99 mmol) of the ethyl ester of glycine (H-Gly-OEt) was added to the mixture at room temperature and lastly 412 mg (2 mmol) of DCC (dicyclohexylcarbodiimide) dissolved in the minimum quantity of dichloromethane was added. The reaction was stirred continuously at room temperature. The process was monitored by HPLC and total consumption of the starting product was observed after one hour. The solvent was removed at low pressure and redissolved in ethyl acetate; precipitation of the corresponding urea was observed and it was then filtered. The reaction crude was purified on a silica gel column with a mixture of hexane/ethyl acetate (75:25) as the eluent. 381 mg of the desired pure product was obtained with a yield of 35%.
  • 19
  • [ 22494-42-4 ]
  • [ 756477-09-5 ]
YieldReaction ConditionsOperation in experiment
96% With [bis(pyridine)iodine]+ tetrafluoroborate In dichloromethane at 20℃; 1 Example 1 5-(2,4-difluorophenyl)-3-iodo-salicylic acid By iodination of 5-(2,4-difluorophenyl)salicylic acid (diflunisal) with the reagent bis(pyridine)iodonium (I) tetrafluoroborate (Ipy2BF4) 357 mg (1.2 mmol) of Ipy2BF4 was added to a solution of 200 mg (0.80 mmol) of diflunisal in 5 ml of dichloromethane at room temperature. It was stirred until the consumption of starting product was observed by HPLC (high performance liquid chromatography). It was diluted in dichloromethane and the product was worked up by acidification with 1 N HCl acid and extraction with dichloromethane. The organic phases were combined and washed with a solution of sodium thiosulphate and then dried over anhydrous magnesium sulphate. The solvent was removed at low pressure and a crude of 98% purity was obtained and then purified by chromatography on silica gel. 290 mg (96% yield) of the desired product was obtained.
86% With chloroamine-T; sodium iodide In acetic acid; acetonitrile at 20℃; for 1.5h; 3 Example 3 5-(2,4-difluorophenyl)-3-iodo-salicylic acid By iodination of 5-(2,4-difluorophenyl)salicylic acid (diflunisal) with chloramine-T (CAT) and sodium iodide. 20 mg (0.08 mmol) of diflunisal, 14 mg (0.093 mmol) of Nal and 30 mg (0-13 mmol) of CAT dissolved in 1040 μl of acetonitrile and 52 μl of acetic acid are placed in a 25 ml flask. It was stirred for 1.5 hr at room temperature. The reaction was monitored by HPLC until the consumption of starting product was observed and 96% of iodinated product was detected. The solution was then acidified to pH = 1.0 with a 5% solution of HCl and extracted with ethyl acetate. The organic phases were combined and washed with a solution of sodium thiosulphate and then dried over anhydrous magnesium sulphate. The solvent was removed at low pressure and a crude of 98% purity was obtained and then purified by chromatography on silica gel. 260 mg (86% yield) of the desired product was obtained.
86% With bis(2,4,6-trimethylpyridine)iodine(I) hexafluorophosphate In dichloromethane at 20℃; 2 Example 2 5-(2,4-difluorophenyl)-3-iodo-salicylic acid By iodination of 5-(2,4-difluorophenyl)salicylic acid (diflunisal) with the reagent bis(2,4,6-trimethylpyridine)iodonium hexafluorophosphate (I) (IColl2PF6) 617 mg (1.2 mmol) of IColl2PF6 was added to a solution of 200 mg (0.80 mmol) of diflunisal in 5 ml of dichloromethane at room temperature. It was stirred until the consumption of starting product was observed by HPLC. It was diluted in dichloromethane and the product was worked up by acidification with 1 N HCl acid and extraction with dichloromethane. The organic phases were combined and washed with a solution of sodium thiosulphate and then dried over anhydrous magnesium sulphate. The solvent was removed at low pressure and a crude of 98% purity was obtained and then purified by chromatography on silica gel. 260 mg (86% yield) of the desired product was obtained.
51% With solid phase supported bis(pyridine)iodonium(I) tetrafluoroborate In methanol at 50℃; Combinatorial reaction / High throughput screening (HTS);
With N-iodo-succinimide; trifluoroacetic acid In acetonitrile at 20℃; 7 Example 7 5-(2,4-difluorophenyl)-3-iodo-salicylic acid By iodination of 5-(2,4-difluorophenyl)salicylic acid (diflunisal) with N-iodosuccinimide (NIS). 198 mg (0.88 mmol, 1.1 eq) of NIS was added at room temperature to a solution of 200 mg (0.8 mmol) of diflunisal in 4 ml of acetonitrile and a catalytic quantity of 18 μl (0.24 mmol, 0.3 eq) of trifluoroacetic acid. It was stirred continuously. The solvent was evaporated at low pressure, it was diluted with dichloromethane and the product was then worked up as in example 1.
With sodium hydroxide; sodium iodide In methanol at 0 - 3℃; 4 Example 4 6-(2,4-difluorophenyl)-3-iodo-salicylic acid By iodination of 5-(2,4-difluorophenyl)salicylic acid (diflunisal) with sodium iodide and sodium hypochlorite An equivalent of sodium iodide (165 mg, 1.1 mmol) and an equivalent of sodium hydroxide (32 mg) were added to a solution of 200 mg (0.80 mmol) of diflunisal in 5 ml of methanol. A 4% solution of sodium hypochlorite was dropwise added to the previous solution over a period of 75 min, keeping the temperature at 0-3 °C. After every addition, a reddish colour was observed which quickly disappeared. It was stirred at this temperature for another hour and treated with a 20% aqueous solution of sodium thiosulphate. A 5% solution of HCl was added and it was extracted with dichloromethane. After the work-up, the product was recrystallized.
With iodine In acetonitrile at 20℃; for 3h; 6 Example 6 5-(2,4-difluorophenyl)-3-iodo-salicylic acid By iodination of 5-(2,4-difluorophenyl)salicylic acid (diflunisal) with iodine and Selectfluor. 200 mg (0.80 mmol) of diffunisal was added to a solution of 354 mg (1 mmol) of Selectfluor and 127 mg (0.5 mmol) of iodine in 10 ml of acetonitrile and the reaction was stirred at room temperature for 3 hr. It was treated with a 20% aqueous solution of sodium thiosulphate. A 5% solution of HCl was added and it was extracted with dichloromethane. After the work-up, the product was recrystallized.
With Iodine monochloride In dichloromethane at 20℃; for 3h; 5 Example 5 5-(2,4-difluorophenyl-3-iodo-salicylic acid By iodination of 5-(2,4-difluorophenyl)salicylic acid (diflunisal) with iodine chloride (ICI). 195 mg (1.2 mmol) of ICI in dichloromethane (1 M) was added at room temperature to a solution of 200 mg (0.80 mmol) of diflunisal in 5 ml of dichloromethane. It was stirred continuously at room temperature for 3 hr and the product was then worked up, as described in example 1.
Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With thallium(I) trifluoroacetate; trifluoroacetic acid at 20℃; for 0.5h; Stage #2: With potassium iodide In water 8 By iodination of 5-(2,4-difluorophenyl)salicylic acid (diflunisal) with thallium trifluoroacetate and potassium iodide. A mixture of 20.6 g of thallium trifluoroacetate (TTFA, 31.9 mmol) and trifluoroacetic acid (TFA, 50 ml) was stirred in a flask until the TTFA dissolved This solution was added at room temperature to a flask containing 51 g (205 mmol) of diflunisal and it was stirred for 30 min. A solution of potassium iodide (Kl, 40.9 g, 245.6 mmol) in 120 ml of water was slowly added to the mixture. After the reaction finished, the product was worked up. First, sodium metabisulphite (NaS2O5, 5.01 g, 26.4 mmol) was added to reduce the species of TI (III) to TI (I), and then a solution of sodium hydroxide was added to neutralize the TFA. It was extracted with dichloromethane and the organic phase was washed with water and dried over magnesium sulphate. The solvent was evaporated at low pressure and a crude was obtained of 96% purity, which was purified by chromatography on a silica gel column using the appropriate eluents.
With [bis(pyridine)iodine]+ tetrafluoroborate In dichloromethane at 20℃; for 1.5h;

  • 20
  • [ 18274-81-2 ]
  • [ 22494-42-4 ]
  • 2',4'-difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylic acid 4-(3H-1,2-dithiole-3-thione-5-yl)-phenyl ester [ No CAS ]
  • [ 2387-23-7 ]
YieldReaction ConditionsOperation in experiment
With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 20h; 2 A IN solution of dicyclohexylcarbodiimide (DCC) in dichloromethane (455 mg, 2.2 mmol) was added to 100 ml of a dichloromethane solution containing of 5- (p- hydroxyphenyl) -3H-1, 2-dithiol-3-thione (451.2 mg, 1.99 mmol) , prepared as described in example 1, diflunisal (500 mg, 1.99 mmol) and 4-dimethylaminopyridine (DMAP) (245 mg, 1.99 mmol) .The mixture was stirred at room temperature under nitrogen for 20 hours. At the end of the reaction dicyclohexylurea (DCU) was removed by filtration.The solution was washed with 0. IN NaOH and cold water. The organic solution was then dried on anhydrous sodium sulphate and evaporated. After removal of the solvent, the mixture was chromatographed on silica gel eluting with a mixture of dichloromethane/ methanol(99.5/0.5) .The compound after washing first with ether, then with ethanol and crystallization with ethyl acetate had a melting point of 202-204 0C
  • 21
  • [ 108-05-4 ]
  • conc. H2 SO4 [ No CAS ]
  • [ 22494-42-4 ]
  • vinyl 5-(2,4-difluorophenyl)salicylate [ No CAS ]
  • 1-(Ethoxycarbonyloxy)ethyl 5-(2,4-fluorophenyl)salicylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium acetate 7.A Step A: Step A: Preparation of vinyl 5-(2,4-difluorophenyl)salicylate 5-(2,4-Difluorophenyl)salicylic acid (1 mol), an excess amount of vinyl acetate (10 mole) and catalytic amounts of Hg(OAc)2 (6 g) and conc. H2 SO4 (0.1 ml) are mixed at room temperature for 5 days. Excess 5-(2,4-difluorophenyl)salicylic acid is removed and sodium acetate is added to neutralize the reaction. Excess vinyl acetate is removed to obtain the product, vinyl 5-(2,4-difluorophenyl) salicylate.
  • 22
  • [ 22494-42-4 ]
  • [ 50893-36-2 ]
  • 1-(ethoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl)-salicylate [ No CAS ]
  • 1-(ethoxycarbonyloxy) 5-(2,4-difluorophenyl)salicylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
2.84 g (91%) With hydrogenchloride; triethylamine; In toluene; EXAMPLE 4 1-(Ethoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl)salicylate Triethylamine (885 mg) was added to a stirred slurry of 5-(2,4-difluorophenyl)salicylic acid in toluene (6.5 ml) under nitrogen. The resulting mixture was stirred for about 2 hours before ethyl 1-chloroethylcarbonate (1.53 g) was added, and the resulting solution heated at reflux until reaction was complete. The reaction mixture was cooled and then added to aqueous hydrochloric acid solution. After thorough mixing, the layers were separated and the organic layers washed with water, dried and filtered. The solvent was removed under reduced pressure, leaving a pale oil which was crystallized from aqueous methanol to afford 2.84 g (91percent) of 1-(ethoxycarbonyloxy) 5-(2,4-difluorophenyl)salicylate, m.p. 79°-80° C.
  • 23
  • [ 22494-42-4 ]
  • [ 50893-36-2 ]
  • 1-(ethoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl)-salicylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In hexane; chloroform; EXAMPLE 2 1-(Ethoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl)salicylate Diflunisal (2.5 g) was dissolved in 30 ml of chloroform containing 1.1 g triethylamine. While stirring at room temperature, ethyl 1-chloroethylcarbonate (1.66 g) was added slowly and the resulting reaction mixture was heated and refluxed for about 67 hours. After cooling, the mixture was concentrated in vacuo. The concentrate was partitioned twice between ether (200 ml) and water, and the organic extracts combined. After chromatography and crystallization as described in Example 1, there was afforded 38.5 g of crystalline product (crystallized from 5percent ethylacetate in hexane), m.p. 79°-80.5° C. (higher melting form II).
  • 24
  • lead (IV) nitrate [ No CAS ]
  • [ 22494-42-4 ]
  • [ 114937-32-5 ]
  • [ 114937-29-0 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; sulfuric acid; sodium hydrogencarbonate In tetrahydrofuran; methanol; sodium hydroxide; hexane; water G G) G) 5-(2,4-difluorophenyl)-salicylaldehyde To a solution of 5-(2,4-difluorophenyl)-salicylic acid (50 g; 0.2 moles) in methyl alcohol (500 ml), conc. sulfuric acid (15 ml) is added dropwise under stirring at room temperature. The mixture is refluxed. After 20 hours the mixture is cooled and concentrated under reduced pressure. The residue is taken up with ethyl ether, washed many times with water and once with a 5% solution of sodium bicarbonate. The organic phase is dried on sodium sulfate and the solvent is removed under reduced pressure. Methyl 5-(2,4-difluorophenyl)-salicylate is so obtained as a solid (54.5 g) which is crystallized from methyl alcohol (500 ml). Yield, 47 g; m.p. = 101-102°C. This ester (47 g) is reduced with lithium aluminum hydride (7.9 g; 0.2 moles) as described for (2RS)-2-[4-(α-hydroxy-benzyl-phenyl)]-propane 1-ol (see point E above). 5-(2,4-difluorophenyl)-salicyl alcohol (41.72 g) is so obtained, which is crystallized from ethyl acetate (200 ml) and then from hexane (180 ml). Yield, 36.9 g (87.7%); m.p. = 143-145°C. An aliquot of this alcohol (2.4 g; 0.01 moles) is dissolved at room temperature in 1N sodium hydroxide (10 ml) and tetrahydrofuran (5 ml). To this solution, lead nitrate (0.5 g) in water (5 ml) and then 10% platinum on carbon (240 mg) are added. This mixture is stirred at 45°C for 30 hours. The mixture is cooled to room temperature, the catalyst is removed by filtration, the solution is made acid (Congo Red) with 10% hydrochloric acid and extracted with ethyl ether. The organic layer is dried on sodium sulfate and the solvent is removed by evaporation under reduced pressure. The desired aldehyde is so obtained as a white solid. Yield, 1.9 g (81%).
  • 25
  • PdCl2 (Fluka) [ No CAS ]
  • [ 89-55-4 ]
  • [ 497-19-8 ]
  • [ 144025-03-6 ]
  • [ 22494-42-4 ]
YieldReaction ConditionsOperation in experiment
70% With triphenylphosphine In ethanol 23.B Preparation of 5-(2,4-difluorophenyl)-salicylic acid from 2,4-difluorophenylboronic acid and palladium tetrakis(triphenylphosphine) B) A mixture of 5-bromosalicylic acid (3 g; 13.8 mmoles), ethanol (2.3 ml), a 2M aqueous sodium carbonate solution (21 ml) and palladium tetrakis(triphenylphosphine) (0.073 g; 0.063 mmoles), prepared from PdCl2 (Fluka) and triphenylphosphine (Fluka), was heated at 80°C. In 10 minutes, a solution of 2,4-difluorophenylboronic acid (2.75 g; titre 94%; 16.4 mmoles), prepared as described in example 20, in ethanol (3.2 ml) was added. At the end of the addition, the reaction mixture was kept under stirring at 80°C for 3 hours. The resultant suspension was filtered obtaining 5-(2,4-difluorophenyl)-salicylic acid (2.8 g; titre 86%; 70% yield).
  • 26
  • [ 111-19-3 ]
  • [ 22494-42-4 ]
  • [ 537048-80-9 ]
YieldReaction ConditionsOperation in experiment
96% Stage #1: sebacoyl chloride; 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With pyridine In tetrahydrofuran at 0℃; for 2h; Stage #2: With hydrogenchloride In tetrahydrofuran; water 5 Pyridine (0.8 mL, 0.010 mol) was added to a mixture of diflunisal (1.16 g, 0.008 mol) and THF (25 mL, 0.308 mol). The mixture was then cooled to OEC by an ice/water bath. Next, the reaction mixture was stirred thoroughly and sebacoyl chloride (1 g, 0.004 mol)/THF (10 mL, 0.123 mol) mixture was added dropwise. The mixture was stirred for 2 hours at 0EC, poured over an ice/water bath, acidified to pH=2 by addition of concentrated HCl (aq.), filtered, and washed with water to yield a white solid. Yield 96%. The melting point range was 162-165EC.Infrared absorption frequencies were 1754, 1658, 1139 and 1104 cm-1. NMR chemical shifts (CDCl3, ppm) δ 8.25 (s, Ar H, 2 H), 7.65 (dd, Ar H, 2 H), 7.4 (td, Ar H, 2 H), 7.2 (d, Ar H, 2 H), 6.95 (m, Ar H, 4H), 2.65 (t, α-CH2, 4 H), 1.8 (p, β-CH2, 4 H), and 1.45 (m, γ-CH2, 4 H).
  • 27
  • [ 21646-49-1 ]
  • [ 22494-42-4 ]
  • [ 537048-82-1 ]
YieldReaction ConditionsOperation in experiment
96% Stage #1: tetradecanedioyl dichloride; 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With pyridine In tetrahydrofuran at 0 - 20℃; for 1h; Stage #2: With hydrogenchloride In tetrahydrofuran; water 7 Pyridine (70. M1, 865 mmol) was added to a solution of diflunisal (71.06 g, 284 mmol) in THF (800 ml). The solution was cooled to 0° C. by an ice/water bath. Next, the reaction was stirred thoroughly and a solution of tetradecanedioyl dichloride (41.6 g, 141 mmol) in THF (130 ml) was added dropwise. The mixture was stirred for 1 hour at room temperature, poured over an ice/water/HCl mixture (final pH 2), filtered, and washed with water to yield a white solid. Yield 96%. The melting point range was 150-151° C.1H-NMR chemical shifts (CDCl3, ppm) δ 8.01 (m, 2H), 7.79 (m, 2H), 7.63 (m, 2H), 7.37 (m, 2H), 7.27 (m, 2H), 7.19 (m, 2H), 2.48 (m, 4H), 1.62 (m, 4H), 1.22 (m, 16H).
  • 28
  • [ 846588-04-3 ]
  • [ 34959-19-8 ]
  • [ 22494-42-4 ]
  • poly(diflunisal-C14-diflunisal-co-DF anhydride) [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: diflunisal-C14-diflunisal diacid chloride; 1,16-hexadecanedioyl dichloride; 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With triethylamine In chloroform at 0 - 4℃; for 1h; Stage #2: With bis(trichloromethyl) carbonate; triethylamine In chloroform at 0 - 4℃; for 2h; 32 Preparation of Random Poly Diflunisal-C14-Diflunisal-coDF Anhydride (DF-C14-DF-coDF Anhydride; Compound 27a) Example 32 Preparation of Random Poly Diflunisal-C14-Diflunisal-coDF Anhydride (DF-C14-DF-coDF Anhydride; Compound 27a) A solution of 6.579 g DF and 7.35 ml TEA in 20.0 ml anhydrous chloroform was slowly added to a solution of 10.000 g compound 15d and 3.895 g compound 12b in 80 ml anhydrous chloroform at 0C+4° C. The reaction mixture was stirred for 1 hour at 0+-4° C., and washed with 100 ml 1N HCl, and 100 ml distilled water. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed in vacuo, and then the solid was dried in a vacuum oven at 40° C. overnight. Fifteen g of the dried polymer were redissolved in 70 ml anhydrous chloroform and 0.625 ml TEA was added to the solution at 0° C. The reaction solution was stirred for 1 hour, and a solution of 87.2 mg triphosgene in 2.0 ml anhydrous chloroform at 0° C. was slowly added. The reaction mixture was stirned for 1 hour at 0+-4° C. and was washed with 100 ml 1N HCl and 100 ml distilled water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed in vacuo at 40° C. The crude polymer was dissolved in 120 ml DCM, and then slowly added to 1.21 anhydrous diethyl ether that was placed in a Teflon cylinder while stirring vigorously. The supemate was decanted, and the residue was washed with anhydrous ethyl ether. The thus obtained gummy polymer was transferred into a Teflon dish and dried in a vacuum oven at 40° C. for 24 hours to obtain 11.4 g of product. Results: [0430] MW=149,000 [0431] PDI=2.36
  • 29
  • C10 bis-L-lactate diol [ No CAS ]
  • [ 846588-02-1 ]
  • [ 22494-42-4 ]
  • poly(DF-C12-DF-co-diflunisal) anhydride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: C10 bis-L-lactate diol; diflunisal-C12-diflunisal diacid chloride With triethylamine In tetrahydrofuran at 30℃; for 12h; Stage #2: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With triethylamine In chloroform at 0℃; for 1h; Stage #3: With bis(trichloromethyl) carbonate; triethylamine In dichloromethane; chloroform at 0℃; for 1h; 37 A solution of 2.755 g CIO-bis-L-lactate diol (Compound 19b) and 3.623 ml anhydrous TEA in 25 ml anhydrous THF was added to 19.00 g of a solution of DF-C 12-DF diacid chloride (Compound 15c) in 125 ml anhydrous THF. The reaction mixture was stirred for 12 hours at 30° C., concentrated in vacuo, co-evaporated twice with 200 ml additional chloroform, and dried in a vacuum oven at 30° C. overnight. The dried intermediate (prepolymer) was re-dissolved in 100 ml anhydrous chloroform, and was cooled to 0° C. in an ice bath. A mixture of 3.466 g DF and 4.058 ml anhydrous TEA was made in 100 ml anhydrous chlofororm, and was slowly added to the pre-polymer solution at 0° C. The reaction mixture was stirred for 1 hour at 0° C., washed with 200 ml 1N HCl and 200 ml distilled water, dried over anhydrous magnesium sulfate, concentrated in vacuo, and dried in a vacuum oven at 40° C. overnight. 0.317 ml anhydrous TEA were added to a solution of 21.6 g intermediate prepolymer in 140 ml DCM, and a solution of 111 mg triphosgene in 5.0 ml anhydrous chlofororm was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 hour, diluted with 40 ml chloroform, washed with 100 ml 1N HCl and twice with 500 ml distilled water, and dried over anhydrous MgSO4. The solution was concentrated in vacuo to about 50 ml, and poured into anhydrous diethyl ether in a Teflon cylinder with stirring to precipitate the product. The supernate was decanted, and the solid was washed with ethyl ether, and dried in a vacuum oven at 40° C. overnight to yield 13.3 g of product. [0443] Results: [0444] MW=120,000 [0445] PDI=1.35
  • 30
  • [ 846588-04-3 ]
  • [ 22494-42-4 ]
  • poly(DF-C14-DF-co-DF) anhydride [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane at 5℃; for 0.5h; 34 Preparation of Random Poly (DF-C14-DF-coDF) Anhydride (Compound 27c) Example 34 Preparation of Random Poly (DF-C14-DF-coDF) Anhydride (Compound 27c) A mixture of 3.971 g DF and 4.64 ml TEA in 18 ml anhydrous DCM was added dropwise to a solution of 10.000 g of DF-C14-DF diacid chloride (Compound 15d) in 30 ml anhydrous DCM at 5° C., and the reaction mixture was stirred for 30 minutes at 5° C. The mixture was then diluted with 40 ml DCM, washed with 100 ml 1N HCl and 100 ml distilled water, and dried over anhydrous magnesium sulfate. The solution was concentrated to about 50 ml in vacuo, and was poured into anhydrous diethyl ether in a Teflon cylinder with stirring to precipitate the product. The supernate was decanted, and the solid was washed with ethyl ether, and dried in a vacuum oven at 40° C. overnight to obtain 9.3 g of the product. Results: [0438] MW=106,000 [0439] PDI=1.88
  • 31
  • [ 64-17-5 ]
  • [ 22494-42-4 ]
  • [ 126093-86-5 ]
YieldReaction ConditionsOperation in experiment
78% With sulfuric acid for 48h; Reflux; 7.1 H2SO4 (1 mL, 18.76 mmol) was added to a solution of diflunisal (1.50 g, 5.995 mmol) in EtOH (50 mL). The reaction mixture was refluxed for 2 days, allowed to reach r.t., and diluted with CH2Cl2 (200 mL). The organic layer was washed with Na2CO3 (1 M aqueous solution, 200 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated to furnish 1.30 g of ethyl 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylate (white solid, yield: 78%).1H NMR (CDCl3, 250 MHz) δ ppm: 10.92 (s, 1H), 7.97 (m, 1H), 7.59 (dt, J1=6.6 Hz, J2=8.5 Hz, 1H), 7.37 (m, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.86-6.99 (m, 2H), 4.44 (c, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H).
78% With sulfuric acid for 48h; Reflux; B-7.1 Step 1 : Ethyl 2,,4,-difluoro-4-hydroxybiphenvl-3-carboxvlate Step 1 : Ethyl 2,,4,-difluoro-4-hydroxybiphenvl-3-carboxvlate H2SO4 (1 mL, 18.76 mmol) was added to a solution of difiunisal ( 1 .50 g, 5.995 mmol) in EtOH (50 mL). The reaction mixture was reflux ed for 2 days, allowed to reach r.t., and diluted with CH2C12 (200 mL). The organic layer was washed with Na2C03 (1 M aqueous solution, 200 mL). It was dried over Na2S04 (anhydrous), filtered and concentrated to furnish 1.30 g of ethyl 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylate (white solid, yield: 78%). NMR (CDCI3, 250 MHz) δ ppm: 10.92 (s, I H), 7.97 (m, 1H), 7.59 (dt, J, = 6.6 Hz, J2 = 8.5 Hz. 1H), 7.37 (m, 1H), 7.05 (d, J = 8.5 Hz, IH), 6.86-6.99 (m, 2H), 4.44 (c, J = 7.1 Hz, 2H), 1.43 (t, J= 7.1 Hz. 3H).
55% With sulfuric acid at 85℃; for 28h;
With sulfuric acid at 80℃; for 18h; 32 Example 32; Preparation of ethyl 4-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy)-2',4'-difluorobiphenyl-3-carboxylate (27); The 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid (1.0 g, 4.0 mmol) was dissolved in ethanol (30 mL) and sulfuric acid (8 mL). The solution was stirred (80° C., 18 h) and then concentrated. The residue was dissolved in ethyl acetate and washed with water, brine and dried over MgSO4. Solvent evaporation afforded 1.0 g of ethyl 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylate. Mass calculated for C15H12F2O3=278.25; found: [M+H]+=279.1.

  • 32
  • [ 22494-42-4 ]
  • [ 344348-56-7 ]
YieldReaction ConditionsOperation in experiment
With thionyl chloride In dichloromethane
With thionyl chloride In toluene at 80℃; for 7h;
With thionyl chloride In tetrahydrofuran for 8h; Reflux; Inert atmosphere; 6 5.6. N-(4-Chloro-2-fluorophenyl)-2',4'-difluoro-4-hydroxybiphenyl-3-carboxamide (6a) 5.6 N-(4-Chloro-2-fluorophenyl)-2',4'-difluoro-4-hydroxybiphenyl-3-carboxamide (6a) To a solution of 4 (0.9 g, 4 mmol) in anhydrous tetrahydrofuran (30 mL) was added dropwise thionyl chloride (1 mL, 14 mmol), and the mixture was refluxed under nitrogen atmosphere for 8 h. After cooling to room temperature, the mixture was steamed to give the intermediate by Dean-Stark apparatus. The residue was carried onto the next step without further purification and it was directly reacted with 4-chloro-2-fluoroaniline (0.5 mL, 4 mmol) in anhydrous tetrahydrofuran (30 mL) for 14 h. After removal of tetrahydrofuran, the reaction mixture was washed with ethyl acetate/n-hexane and the crude product was extraction with ethyl acetate (3 * 25 mL), washed with 10% NaHCO3 (15 mL), H2O (3 * 25 mL), brine (10 mL), and then dried over anhydrous MgSO4. The organic layer was collected, dried over anhydrous MgSO4, and then concentrated in vacuo. The crude product was washed and purified by crystallization from hot ethanol to obtain 6a as white powder (yield 30%). Mp: 245-246 °C (EtOH); IR (KBr, νmax cm-1): 1637 (CO), 3127 (NH), 3300 (OH); 1H NMR (300 MHz, DMSO-d6): δ ppm 7.12 (d, J = 6.0 Hz, 1H), 7.19 (td, J = 9.0, 1.8 Hz), 7.31-7.40 (m, 2H), 7.55-7.64 (m, 3H), 8.14 (t, J = 1.5 Hz, 1H), 8.24 (t, J = 8.7 Hz, 1H), 10.77 (s, 1H), 12.19 (s, 1H); 13C NMR (75 MHz, DMSO-d6): δ ppm 104.51, 112.07, 116.20, 117.66, 123.92, 124.04, 125.41, 128.15, 130.49, 131.58, 134.23, 151.85, 154.31, 157.78, 160.26, 162.71, 164.25; HPLC purity: >95%, tR = 9.07 min; HRMS (EI) m/z:calcd [M]+, 377.0430 (C19H11ClF3NO2+), found, 377.0433.
With thionyl chloride In tetrahydrofuran for 6h; Reflux; Inert atmosphere; Dean-Stark; 5.3. General procedure I: Preparation of compounds (2a-2l) To a solution of diflunisal (0.9 g, 4 mmol) in anhydrous tetrahydrofuran(30 mL) was added dropwise thionyl chloride (1 mL,14 mmol), and the mixture was refluxed under nitrogen atmospherefor 6 h. After cooling to room temperature, the mixturewas steamed to give the intermediate by Dean-Stark apparatus.The residue was carried onto the next step without further purificationand it was directly reacted with various anilines (4 mmol) inanhydrous tetrahydrofuran (30 mL) for 12-14 h. After removal oftetrahydrofuran, the reaction mixture was washed with ethyl acetate/n-hexane and the crude product was extraction with ethylacetate (3 25 mL), washed with 10% NaHCO3 (15 mL), H2O(3 25 mL), brine (10 mL), and then dried over anhydrousMgSO4. The organic layer was collected and concentrated in vacuo.The crude product was washed and purified by crystallization fromhot ethanol to obtain compounds (2a-2l). The physicochemicalcharacterizations of intermediates 2a-2l are reported in theliterature.60

  • 33
  • [ 1204436-17-8 ]
  • [ 22494-42-4 ]
  • [ 1204436-00-9 ]
YieldReaction ConditionsOperation in experiment
With dicyclohexyl-carbodiimide In dichloromethane at 0℃; 3.2 Step 2:; DMAP (0.2 mmoL) and DCC (1.1 mmol) is added to a solution of compound 3d (1.0 mmol) and 3c (1.0 mmol) in CH2CI2 (6 ml_) at 0 0C. The reaction mixture is stirred for 8 hours before it is filtered through celite. The solvent is removed under reduced presure and the residue is purified using flash chromatography with EtOAc/hexane as the eluting solvent to give compound 3.
  • 34
  • [ 616-91-1 ]
  • [ 22494-42-4 ]
  • [ 96325-00-7 ]
YieldReaction ConditionsOperation in experiment
24% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With triethylamine In acetone at -10 - 9℃; for 0.416667h; Stage #2: With 2,2,2-Trichloroethyl chloroformate In acetone at -10 - 0℃; for 2h; Stage #3: N-acetylcystein With triethylamine In acetone at -12 - 15℃; 13a Example 13a Example 13aTo a solution of 2',4'-difluoro-4-hydroxy-1,1'-diphenyl-3-carboxylic acid (Diflunisal, 82.5 g, 0.329 mol) dissolved in acetone (450 mL) and cooled to -10° C. (refrigerant mixture: ice-EtOH) was added Et3N (101 mL, 0.725 mol) slowly (addition: 25 min, internal temperature: from -8° C. to 9° C.). To the resulting solution was added 2,2,2-trichloroethyl chloroformate (100 mL, 0.725 mol) slowly (addition: 60 min, internal temperature was maintained below 0° C.: from -10° C. to 0° C.). The mixture was stirred for 1 h at 0° C. (a white precipitate of triethylamine hydrochloride was gradually formed). At the end of the reaction, the mixture was filtered under vacuum, the precipitate (triethylamine hydrochloride) was washed with acetone (4×180 mL) and the filtrate was evaporated under vacuum at 30° C. The oily residue was taken with Et2O (150 mL) and the suspension was evaporated again under vacuum. The operation was repeated three times to remove excess of chlorocarbonate. The residue was dissolved in acetone (180 mL), and added to a refrigerated solution of N-acetyl-L-cysteine (N-Ac-Cys, 53.81 g, 0.329 mol) and Et3N (46 mL, 0.329 mol) in acetone (140 mL) slowly (addition: 55 min, internal temperature was maintained below 15° C.: from 0° C. to 15° C.). The reaction mixture was stirred at 15° C. for 4 h. The mixture was cooled to -12° C. (internal temperature), and Et3N (115 mL, 0.824 mol) was added. The mixture was stirred for 15 h at -12° C. (internal temperature), and at the end of the reaction, the mixture was filtered under vacuum and the precipitate was washed with acetone (3×150 mL). The oily precipitate was suspended in CH2Cl2 (400 mL), cooled to 0° C. and an aqueous HCl solution (15% v:v) was added with vigorous stirring until the pH was lowered to 3. Ethanol (80 mL) was added, and the aqueous phase was extracted with CH2Cl2 (2×400 mL). The combined organic layers were washed with a 10% HCl aqueous solution (1×500 mL) and with water (2×600 mL), were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by trituration with Et2O (100 mL), affording 44.13 g of the title compound (HPLC purity: 88.26%) To increase purity, the solid was suspended in Et2O (100 mL) and stirred at room temperature for 20 min. The solid was filtered under vacuum and was washed with Et2O (3×100 mL), to afford 31.33 g of the title compound GMC-3b (Rf=0.3 CH2Cl2/MeOH/AcOH 95:5:1), white solid, 24% yield, 96.22% HPLC purity); Purity was determined by NMR analysis and mass spectrometry to conform to the following parameters: 1H-NMR (CD3OD, 250 MHz, δ): 8.00 (m, 1H, ArH); 7.66 (dm, J=8.2 Hz, 1H, ArH); 7.50 (m, 1H, ArH); 7.06 (m, 3H, ArH); 4.74 (m, 1H, CH); 3.77 (dd, J=4.7 and 13.7 Hz, 1H, CH); 3.40 (m, 1H, CH); 1.98 (s, 3H, CH3); MS-EI+m/z: 396.00 (M+1); LC-MS: M+1: 396.00; purity: 96.52% (HPLC method: SunFire C18 3.5 um, 2.1×100 mm, flow: 0.3 mL/min, gradient: A:B 3 min 10:90+ from 10:90 to 95:5 in 17 min+10 min 95:5; A: CH3CN:MeOH 1:1; B: NH4OAc buffer 5 mM pH 7).
24% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With triethylamine; 2,2,2-Trichloroethyl chloroformate In acetone at -10 - 0℃; for 2h; Stage #2: N-acetylcystein In acetone at -12 - 15℃; for 20h; A-13a Example A- 13a Example A-13a To a solution of 2'.4'-di†luoro-4-hydroxy- 1 , 1 '-diphenyl-3-carboxylie acid (Diflunisal, 82.5 g. 0.329 mol) dissolved in acetone (450 niL) and cooled to -10 °C (refrigerant mixture: ice-EtOH) was added Et3N (101 mL, 0.725 mol) slowly (addition: 25 min, internal temperature: from -8 °C to 9 °C). To the resulting solution was added 2,2,2-trichloroethyl chloro ormate (100 mL, 0.725 mol) slowly (addition: 60 min, internal temperature was maintained below 0°C: from -10 °C to 0 °C). The mixture was stirred for 1 h at 0 CC (a white precipitate of triethylamine hydrochloride was gradually formed ). At the end of the reaction, the mixture was filtered under vacuum, the precipitate (triethylamine hydrochloride) was washed with acetone (4x180 mL) and the filtrate was evaporated under vacuum at 30 °C. The oily residue was taken with Et20 (150 mL) and the suspension was evaporated again under vacuum. The operation was repeated three times to remove excess of chlorocarbonate. The residue was dissolved in acetone (180 mL), and added to a refrigerated solution of N- acetyl-Z-cysteine (N-Ac-Cys, 53.81 g, 0.329 mol) and Et3N (46 mL, 0.329 mol) in acetone (140 mL) slowly (addition: 55 min, internal temperature was maintained below 15°C: from 0 °C to 1 5 °C). The reaction mixture was stirred at 15 °C for 4 h. The mixture was cooled to - 12 °C (internal temperature), and Et3N (1 15 mL, 0.824 mol) was added. The mixture was stirred for 15 h at -12 °C (internal temperature), and at the end of the reaction, the mixture was filtered under vacuum and the precipitate was washed with acetone (3x150 mL). The oily precipitate was suspended in CH2C12 (400 mL), cooled to 0 °C and an aqueous HCl solution (15% v:v) was added with vigorous stirring until the pH was lowered to 3. Ethanol (80 mL) was added, and the aqueous phase was extracted with CTLCL (2x400 mL). The combined organic layers were washed with a 10% HCl aqueous solution (1x500 mL) and with water (2x600 mL), were dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by trituration with Et20 (100 mL), affording 44.13 g of the title compound (HPLC purity: 88.26%) To increase purity, the solid was suspended in Et20 (100 mL) and stirred at room temperature for 20 min. The solid was filtered under vacuum and was washed with Et20 (3x100 mL), to afford 31.33 g of the title compound GMC-252 (R/= 0.3 CH2Cl2/MeOH/AcOH 95:5: 1 ), white solid, 24% yield, 96.22% HPLC purity); Purity was determined by NMR analysis and mass spectrometry to conform to the following parameters: 1H-NMR (CD3OD, 250 MHz, δ): 8.00 (m, 1H, ArH); 7.66 (dm. J = 8.2 Hz, 1H, ArH); 7.50 (m, 1H, ArH); 7.06 (m, 3H, ArH); 4.74 (m, 1H, CH); 3.77 (dd, J= 4.7 and 13.7 Hz, 1H, CH); 3.40 (m, 1H, CH); 1.98 (s, 3H, CH3); MS-EI+ m/z: 396.00 (M+l); LC-MS: M+l : 396.00; purity: 96.52% (HPLC method: SunFire C18 3.5 um, 2.1x100 mm, flow: 0.3 mL/min, gradient: A:B 3 min 10:90 + from 10:90 to 95:5 in 17 min + 10 min 95:5; A: CH3CN:MeOH 1 : 1 ; B: NH4OAc buffer 5 raM pH 7).
  • 35
  • [ 55544-00-8 ]
  • [ 22494-42-4 ]
YieldReaction ConditionsOperation in experiment
99% With potassium hydroxide In water at 80℃; for 3h; Green chemistry;
98% With potassium hydroxide In tetrahydrofuran; water at 80℃; for 3h;
90% Stage #1: methyl 2',4'-difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylate With potassium hydroxide In water for 0.5h; Reflux; Stage #2: With hydrogenchloride In water
89% With water; lithium hydroxide In tetrahydrofuran; methanol
With lithium hydroxide monohydrate In tetrahydrofuran; methanol; water at 20℃; for 5h; 5.5. 2',4'-Difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (4) To a solution of 3 (1.39 g, 5 mmol) in dichloromethane (50 mL) at -78 °C was added dropwise boron tribromide (5.62 mL, 32.94 mmol) for 5-10 min. The reaction mixture was stirred overnight at room temperature. Upon completion, the reaction was quenched with H2O (30 mL), extracted with dichloromethane (3 x 30 mL), brine (10 mL), dried over anhydrous MgSO4, and then concentrated in vacuo. The residue was carried onto the next step without further purification. To a solution of residue in tetrahydrofuran/methanol/water (1:1:1) was added lithium hydroxide monohydrate (1.42 g, 15 mmol). The reaction was stirred at room temperature upon completion. And then, the reaction was acidified with 30% HCl (aq), extracted with ethyl acetate (3 x 25 mL), dried over MgSO4, and then concentrated in vacuo. The residue was purifiedby flash chromatography (CH2Cl2, 1% MeOH, 0.2% acetic acid) to obtain 4 as a white solid (yield 43%).

  • 36
  • [ 22494-42-4 ]
  • [ 100-39-0 ]
  • [ 1381777-23-6 ]
YieldReaction ConditionsOperation in experiment
77% With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; for 18h; 3.1 BnBr (1.35 mL, 11.286 mmol) was added to a solution of diflunisal (2.0 g, 7.99 mmol) in TBAF (10 mL, 1 M solution in THF) and the reaction mixture was stirred at r.t. overnight (18 h). The organic layer was poured into H2O (15 mL) and extracted with EtOAc (40 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (hexanes) to furnish 2.09 g of benzyl 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylate (white solid, yield: 77%).1H NMR (CDCl3, 250 MHz) δ ppm: 10.84 (s, 1H), 8.00 (s, 1H), 7.60 (m, 1H), 7.29-7.47 (m, 6H), 7.06 (d, J=8.4 Hz, 1H), 6.91 (m, 2H), 5.42 (s, 2H).
77% With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; for 18h; B-3.1 Step 1 : Benzyl 2'.4'-ditluoro-4-hvdroxvbiphenvl-3 -carboxvlate Step 1 : Benzyl 2'.4'-ditluoro-4-hvdroxvbiphenvl-3 -carboxvlate BiiBr (1.35 mL, 1 1 .286 mmol) was added to a solution of dillunisal (2.0 g, 7.99 mmol) in TBAF (10 mL. 1 M solution in THF) and the reaction mixture was stirred at r.t. overnight (18 h). The organic layer was poured into H20 ( 15 mL) and extracted with EtOAc (40 mL). It was dried over Na2S04 (anhydrous), filtered and concentrated. The crude residue was flash ehromatographed on SiO? (hexanes) to furnish 2.09 g of benzyl 2'.4'-difiuoro-4- hydroxybiphenyl-3-carboxylate (white solid, yield: 77%). NMR (CDCI3, 250 MHz) δ ppm: 10.84 (s, 1H), 8.00 (s, 1H), 7.60 (m, 1H), 7.29-7.47 (m, 6H), 7.06 (d, J= 8.4 Hz, 1H), 6.91 (m, 2H), 5.42 (s, 2H).
  • 37
  • [ 71-23-8 ]
  • [ 22494-42-4 ]
  • [ 666734-49-2 ]
YieldReaction ConditionsOperation in experiment
76% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 50℃; for 2h; Stage #2: propan-1-ol In N,N-dimethyl-formamide at 50℃; for 3h; 8.1 CDI (972 mg, 5.99 mmol) was added to a solution of diflunisal (1.50 g, 5.99 mmol) in DMF (30 mL). The reaction mixture was stirred at 50° C. for 2 h and n-PrOH (1.13 mL, 14.97 mmol) was dropwise added. The reaction mixture was stirred at 50° C. for 3 h and allowed to reach r.t. It was poured into H2O (50 mL) and extracted with Et2O (2×50 mL). The organic layer was washed with NaHCO3 (20 mL, saturated aqueous solution), dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (2% EtOAc/hexanes) to furnish 1.33 g of propyl 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylate (yellow-coloured oil, yield: 76%).1H NMR (CDCl3, 250 MHz) δ ppm: 10.92 (s, 1H), 7.98 (m, 1H), 7.59 (dt, J1=6.9 Hz, J2=8.8 Hz, 1H), 7.36 (m, 1H), 7.05 (d, J=8.8 Hz, 1H), 6.86-7.00 (m, 2H), 4.33 (t, J=6.6 Hz, 2H), 1.82 (m, 2H), 1.04 (t, J=7.4 Hz, 3H).
76% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 50℃; for 2h; Stage #2: propan-1-ol In N,N-dimethyl-formamide at 50℃; for 3h; B-8.1 Step 1 : Propyl 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylate Step 1 : Propyl 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylate GDI (972 mg, 5.99 mmol) was added to a solution of diflunisal (1.50 g, 5.99 mmol) in DMF (30 mL). The reaction mixture was stirred at 50 °C for 2 h and n-PrOH (1.13 mL, 14.97 mmol) was dropwise added. The reaction mixture was stirred at 50 °C for 3 h and allowed to reach r.t. It was poured into H20 (50 mL) and extracted with Et20 (2x50 mL). The organic layer was washed with NaHC03 (20 mL, saturated aqueous solution), dried over Na2S04 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO (2% EtOAc/hexanes) to furnish 1 .33 g f propyl 2'.4'-ditluoro-4-hydroxybiphenyl-3- carboxylate (yellow-coloured oil, yield: 76%). 1H NMR (CDC13, 250 MHz) 6 ppm: 10.92 (s, 1 H). 7.98 (m, 1H), 7.59 (dt, J/ - 6.9 Hz. J2 = 8.8 Hz, 1H), 7.36 (m, 1H), 7.05 (d, J = 8.8 Hz, 1H), 6.86-7.00 (m, 2H). 4.33 (t, J= 6.6 Hz, 2H), 1.82 (m, 2H), 1.04 (t, J= 7.4 Hz, 3H).
  • 38
  • [ 22494-42-4 ]
  • [ 67-63-0 ]
  • [ 1381777-24-7 ]
YieldReaction ConditionsOperation in experiment
41% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 50℃; for 2h; Stage #2: isopropyl alcohol In N,N-dimethyl-formamide at 50℃; for 3h; 9.1 CDI (972 mg, 5.99 mmol) was added to a solution of diflunisal (1.50 g, 5.99 mmol) in DMF (30 mL). The reaction mixture was stirred at 50° C. for 2 h and isopropyl alcohol (1.15 mL, 14.97 mmol) was dropwise added. The reaction mixture was stirred at 50° C. for 3 h and allowed to reach r.t. It was poured into H2O (50 mL) and extracted with Et2O (2×60 mL). The organic layer was washed with NaHCO3 (20 mL, saturated aqueous solution), dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (15% EtOAc/hexanes) to furnish 720 mg of isopropyl 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylate (white solid, yield: 41%).1H NMR (CDCl3, 250 MHz) δ ppm: 11.03 (s, 1H), 7.94 (m, 1H), 7.58 (dt, J1=8.5 Hz, J2=8.0 Hz, 1H), 7.37 (m, 1H), 7.05 (d, J=8.8 Hz, 1H), 6.93 (m, 2H), 5.31 (m, 1H), 1.41 (s, 3H), 1.39 (s, 3H).
41% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 50℃; for 2h; Stage #2: isopropyl alcohol In N,N-dimethyl-formamide at 50℃; for 3h; B-9.1 Step 1 : Isopropyl 2\4'-difluoro-4-hvdroxybiphenyl-3-carboxylate Step 1 : Isopropyl 24'-difluoro-4-hvdroxybiphenyl-3-carboxylate CD I (972 mg, 5.99 mmol) was added to a solution of ditlunisal (1.50 g, 5.99 mmol) in DMF (30 mL). The reaction mixture was stirred at 50 °C for 2 h and isopropyl alcohol (1.15 mL, 14.97 mmol) was dropwise added. The reaction mixture was stirred at 50 °C for 3 h and allowed to reach r.t. It was poured into H20 (50 mL) and extracted with Et20 (2x60 mL). The organic layer was washed with NaHC03 (20 mL, saturated aqueous solution), dried over Na;S04 (anhydrous), filtered and concentrated. The crude residue was flash chromato graphed on Si02 (15% EtOAc/hexanes) to furnish 720 mg of isopropyl 2',4'-difluoro-4- hydroxybiphenyl-3-carboxylate (white solid, yield: 41 %). NMR (CDC13, 250 MHz) 8 ppm: 1 1 .03 (s, 1H), 7.94 (m, 1H), 7.58 (dt, J, - 8.5 Hz, J2 = 8.0 Hz, 1H), 7.37 (m. 1 H). 7.05 (d, J = 8.8 Hz, 1H), 6.93 (m, 2H), 5.3 1 (m, 1H), 1 .41 (s, 3H), 1 .39 (s, 3H).
  • 39
  • [ 22494-42-4 ]
  • [ 2746-25-0 ]
  • [ 1381777-26-9 ]
YieldReaction ConditionsOperation in experiment
83% With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; for 16h; 17.1 PMBBr (1.20 mL, 8.325 mmol) was added to a solution of diflunisal (1.50 g, 5.995 mmol) in TBAF (7 mL, 1 M solution in THF) and the mixture was stirred at r.t. overnight (16 h). The reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (70 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5→10% EtOAc/hexanes) to furnish 1.85 g of 4-methoxybenzyl 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylate (white solid, yield: 83%).1H NMR (CDCl3, 250 MHz) δ ppm: 10.89 (s, 1H), 7.96 (bs, 1H), 7.58 (dt, J1=8.6 Hz, J2=1.9 Hz, 1H), 7.39 (d, J=8.9 Hz, 2H), 7.33 (m, 1H), 7.05 (d, J=8.6 Hz, 1H) 6.98-6.83 (m, 4H), 5.34 (s, 2H), 3.81 (s, 3H).
83% With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; for 16h; B-17.1 Step 1 : 4-Methoxvbenzyl 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylate Step 1 : 4-Methoxvbenzyl 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylate PMBBr (1.20 mL. 8.325 mmol) was added to a solution of diflunisal (1.50 g, 5.995 mmol) in TBAF (7 mL, 1 M solution in THF) and the mixture was stirred at r.t. overnight (16 h). The reaction mixture was poured into FLO (100 mL) and extracted with EtOAc (70 mL). It was dried over Na2S04 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on Si02 (5- 10% EtOAc/hexanes) to furnish 1.85 g of 4-methoxybenzyl 2,,4'-difluoro-4-hydroxybiphenyl-3-carboxylate (white solid, yield: 83%). lU NMR (CDC13, 250 MHz) δ ppm: 10.89 (s, 1H), 7.96 (bs, 1H), 7.58 (dt, J/ = 8.6 Hz, J2 = 1.9 Hz, 1H), 7.39 (d, J = 8.9 Hz, 2H), 7.33 (m, 1H), 7.05 (d, J = 8.6 Hz, 1H) 6.98- 6.83 (m, 4H), 5.34 (s, 2H), 3.81 (s, 3H).
  • 40
  • [ 22494-42-4 ]
  • [ 75-65-0 ]
  • [ 1381777-25-8 ]
YieldReaction ConditionsOperation in experiment
70% With dmap; dicyclohexyl-carbodiimide In dichloromethane; toluene at 20℃; for 60h;
68% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 50℃; for 0.5h; Stage #2: <i>tert</i>-butyl alcohol With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 50℃; for 20h; 14.1 CDI (1.29 g, 7.99 mmol) was added to a solution of diflunisal (2.02 g, 8.07 mmol) in DMF (20 mL). The reaction mixture was stirred at 50° C. for 30 min and tert-butyl alcohol (1.50 mL, 14.97 mmol) and DBU (2.40 mL, 16.064 mmol) were dropwise added. The reaction mixture was stirred at 50° C. for 20 h and allowed to reach r.t. It was poured into NaHCO3 (100 mL, saturated aqueous solution) and extracted with EtOAc (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5% EtOAc/hexanes) to furnish 1.677 g of ten-butyl 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylate (colourless oil, yield: 68%).1H NMR (CDCl3, 250 MHz) δ ppm: 11.40 (s, 1H), 7.88 (m, 1H), 7.55 (dt, J=8.8 Hz, 1H), 7.36 (m, 1H), 6.86-7.04 (m, 3H), 1.62 (s, 9H).
68% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 50℃; for 0.5h; Stage #2: <i>tert</i>-butyl alcohol With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 50℃; for 20h; B-14.1 Step 1 : /tvv-Butyl 2'.4'-difluoro-4-hvdroxybiphenvl-3-carboxvlate Step 1 : /tvv-Butyl 2'.4'-difluoro-4-hvdroxybiphenvl-3-carboxvlate CDI (1.29 g. 7.99 mmol) was added to a solution of diflunisal (2.02 g, 8.07 mmol) in DMF (20 mL). The reaction mixture was stirred at 50 °C for 30 min and tert-butyl alcohol ( 1.50 mL, 14.97 mmol) and DBU (2.40 mL, 16.064 mmol) were dropwise added. The reaction mixture was stirred at 50 °C for 20 h and allowed to reach r.t. It was poured into NaHC03 (100 mL, saturated aqueous solution) and extracted with EtOAc (100 mL). The organic layer was dried over a2S04 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on Si02 (5% EtOAc Tiexanes) to furnish 1.677 g of tert-butyl 2',4'-difluoro- 4-hydroxybiplienyl-3-carboxylate (colourless oil, yield: 68%). 1H NMR (CDC13, 250 MHz) δ ppm: 11.40 (s, 1H), 7.88 (m, 1H), 7.55 (dt, J = 8.8 Hz, 1H), 7.36 (m, 1H), 6.86-7.04 (m, 3H), 1.62 (s, 9H).
  • 41
  • methyl 2',4'-difluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylate [ No CAS ]
  • [ 22494-42-4 ]
YieldReaction ConditionsOperation in experiment
99% Stage #1: methyl 2',4'-difluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylate With boron tribromide In dichloromethane at -78℃; for 1h; Inert atmosphere; Stage #2: With sodium hydroxide In methanol for 4h; Reflux;
99% With trimethylsilan
99% Stage #1: methyl 2',4'-difluoro-4-methoxy-[1,1'-biphenyl]-3-carboxylate With boron tribromide In tetrahydrofuran at -20℃; for 2h; Stage #2: With sodium hydroxide at 80℃; for 4h;
Multi-step reaction with 2 steps 1: boron tribromide / dichloromethane / 5 h / -78 - 20 °C / Inert atmosphere 2: lithium hydroxide monohydrate / tetrahydrofuran; methanol; water / 5 h / 20 °C

  • 42
  • [ 22494-42-4 ]
  • [ 367-25-9 ]
  • [ 1468402-80-3 ]
YieldReaction ConditionsOperation in experiment
42% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With thionyl chloride In tetrahydrofuran for 8h; Reflux; Inert atmosphere; Stage #2: 2,4-difluorophenylamine In tetrahydrofuran for 14h; 2 N-(2,4-difluorophenyl)-2',4'-difluoro-4-hydroxybiphenyl-3-carboxamide (compound 2) Thionyl chloride (1 mL, 14 mmol) was added to disfunisal (0.9 g, 4 mmol) in anhydrous tetrahydrofuran (30 mL), and the mixture was refluxed under nitrogen atmosphere for 8 h. After cooling to room temperature, the mixture was steamed to give the intermediate by Dean-Stark apparatus, which residue was used directly in the next step. Freshly prepared intermediate was directly reacted with 2,4-difluoroaniline (0.4 mL, 4 mmol) in anhydrous tetrahydrofuran (30 mL) for 14 h. After removal of tetrahydrofuran, the reaction mixture was washed with ethyl acetate/hexane and the crude product was extracted in ethyl acetate. The organic layer was collect and dried over anhydrous Na2SO4, and then the solvent was evaporated. The crude product was washed and purified by crystallization from hot ethanol to afford compound 2. Yield: 42%. Mp: 233-234° C. (EtOH). 1H-NMR (300 MHz, DMSO-d6): δ ppm 7.10-7.23 (m, 3H, Ar-H5,6',6"), 7.33-7.45 (m, 2H, Ar-H5',5"), 7.55-7.64 (m, 2H, Ar-H6,3'), 8.06-8.15 (m, 2H, Ar-H2,3"), 10.64 (s, 1H, NH), 12.1.6 (s, 1H, OH). HRMS (EI) m/z: calcd [M]+, 361.0726 (C19H11F4NO2+). found, 361.0730.
  • 43
  • [ 22494-42-4 ]
  • [ 3863-11-4 ]
  • [ 1468402-81-4 ]
YieldReaction ConditionsOperation in experiment
61% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With thionyl chloride In tetrahydrofuran for 8h; Reflux; Inert atmosphere; Stage #2: 3,4-difluoroaniline In tetrahydrofuran for 14h; 3 N-(3,4-difluorophenyl)-2',4'-difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxamide (compound 3) Thionyl chloride (1 mL, 14 mmol) was added to disfunisal (0.9 g, 4 mmol) in anhydrous tetrahydrofuran (30 mL), and the mixture was refluxed under nitrogen atmosphere for 8 h. After cooling to room temperature, the mixture was steamed to give the intermediate by Dean-Stark apparatus, which residue was used directly in the next step. Freshly prepared intermediate was directly reacted with 3,4-difluoroaniline (0.4 mL, 4 mmol) in anhydrous tetrahydrofuran (30 mL) for 14 h. After removal of tetrahydrofuran, the reaction mixture was washed with ethyl acetate/hexane and the crude product was extracted in ethyl acetate. The organic layer was collect and dried over anhydrous Na2SO4, and then the solvent was evaporated. The crude product was washed and purified by crystallization from hot ethanol to afford compound 3. Yield: 61%. Mp: 231-232° C. (EtOH). 1H-NMR (300 MHz, DMSO-d6): δ ppm 7.09 (d, J=8.7 Hz, 1H, Ar-H5), 7.20 (td, J=8.4, 3 Hz, 1H, Ar-H6'), 7.45-7.49 (m, 3H, Ar-H3',5,6"), 7.56-7.64 (m, 2H, Ar-H6,5"), 7.87-7.93 (m, 1H, Ar-H6"), 8.01 (t, J=0.9 Hz, 1H, Ar-H2), 10.55 (s, 1H, NH), 11.70 (s, 1H, OH). HRMS (EI) m/z: calcd [M]+, 361.0726 (C19H11F4NO2+). found, 361.0724.
  • 44
  • [ 22494-42-4 ]
  • [ 367-30-6 ]
  • [ 1468402-82-5 ]
YieldReaction ConditionsOperation in experiment
37% Example 4 N-(2,5-difluorophenyl)-2?,4?-difluoro-4-hydroxy-[1,1?-biphenyl]-3-carboxamide (compound 4) [0061] Thionyl chloride (1 mL, 14 mmol) was added to disfunisal (0.9 g, 4 mmol) in anhydrous tetrahydrofuran (30 mL), and the mixture was refluxed under nitrogen atmosphere for 8 h. After cooling to room temperature, the mixture was steamed to give the intermediate by Dean-Stark apparatus, which residue was used directly in the next step. Freshly prepared intermediate was directly reacted with <strong>[367-30-6]2,5-difluoroaniline</strong> (0.4 mL, 4 mmol) in anhydrous tetrahydrofuran (30 mL) for 14 h. After removal of tetrahydrofuran, the reaction mixture was washed with ethyl acetate/hexane and the crude product was extracted in ethyl acetate. The organic layer was collect and dried over anhydrous Na2SO4, and then the solvent was evaporated. The crude product was washed and purified by crystallization from hot ethanol to afford compound 4. [0064] Yield: 37%. Mp: 213-214 C. (EtOH). 1H-NMR (300 MHz, DMSO-d6): delta ppm 6.99-7.05 (m, 1H, Ar-H4?), 7.12-7.22 (m, 2H, Ar-H5,6?), 7.33-7.44 (m, 2H, Ar-H5?,3?), 7.55-7.65 (m, 2H, Ar-H6,3?), 8.14-8.23 (m, 2H, Ar-H2,6?), 10.89 (s, 1H, NH), 12.22 (s, 1H, OH). HRMS (EI) m/z: calcd [M]+, 361.0726 (C19H11F4NO2+). found, 361.0731.
  • 45
  • [ 22494-42-4 ]
  • [ 88-17-5 ]
  • [ 1468402-83-6 ]
YieldReaction ConditionsOperation in experiment
36% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With thionyl chloride In tetrahydrofuran for 8h; Reflux; Inert atmosphere; Stage #2: 2-(trifluoromethyl)benzenamine In tetrahydrofuran for 14h; 5 Example 5 2′,4′-difluoro-4-hydroxy-N-(2-(trifluoromethyl)phenyl)-[1,1′-biphenyl]-3-carboxamide (compound 5) Example 5 2′,4′-difluoro-4-hydroxy-N-(2-(trifluoromethyl)phenyl)-[1,1′-biphenyl]-3-carboxamide (compound 5) [0065] Thionyl chloride (1 mL, 14 mmol) was added to disfunisal (0.9 g, 4 mmol) in anhydrous tetrahydrofuran (30 mL), and the mixture was refluxed under nitrogen atmosphere for 8 h. After cooling to room temperature, the mixture was steamed to give the intermediate by Dean-Stark apparatus, which residue was used directly in the next step. Freshly prepared intermediate was directly reacted with 2-(trifluoromethyl)aniline (0.5 mL, 4 mmol) in anhydrous tetrahydrofuran (30 mL) for 14 h. After removal of tetrahydrofuran, the reaction mixture was washed with ethyl acetate/hexane and the crude product was extracted in ethyl acetate. The organic layer was collect and dried over anhydrous Na2SO4, and then the solvent was evaporated. The crude product was washed and purified by crystallization from hot ethanol to afford compound 5. [0068] Yield: 36%. Mp: 180-181° C. (EtOH). 1H-NMR (300 MHz, DMSO-d6): δ ppm 7.11-7.22 (m, 2H, Ar-H5,6′), 7.32-7.43 (m, 2H, Ar-H5′,3′), 7.54-7.65 (m, 2H, Ar-H6,3′), 7.70-7.78 (m, 2H, Ar-H4″,5″), 8.18-8.20 (m, 2H, Ar-H2,6″), 10.81 (s, 1H, NH), 12.19 (s, 1H, OH). HRMS (EI) m/z: calcd [M]+, 393.0788 (C20H12F5NO2+). found, 393.0784.
  • 46
  • [ 22494-42-4 ]
  • [ 98-16-8 ]
  • 2',4'-difluoro-4-hydroxy-N-(3-(trifluoromethyl)phenyl)-[1,1'-biphenyl]-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
32% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With thionyl chloride In tetrahydrofuran for 8h; Reflux; Inert atmosphere; Stage #2: 3-trifluoromethylaniline In tetrahydrofuran for 14h; 6 Example 6 2′,4′-difluoro-4-hydroxy-N-(3-(trifluoromethyl)phenyl)-[1,1′-biphenyl]-3-carboxamide (compound 6) Example 6 2′,4′-difluoro-4-hydroxy-N-(3-(trifluoromethyl)phenyl)-[1,1′-biphenyl]-3-carboxamide (compound 6) [0069] Thionyl chloride (1 mL, 14 mmol) was added to disfunisal (0.9 g, 4 mmol) in anhydrous tetrahydrofuran (30 mL), and the mixture was refluxed under nitrogen atmosphere for 8 h. After cooling to room temperature, the mixture was steamed to give the intermediate by Dean-Stark apparatus, which residue was used directly in the next step. Freshly prepared intermediate was directly reacted with 3-(trifluoromethyl)aniline (0.5 mL, 4 mmol) in anhydrous tetrahydrofuran (30 mL) for 14 h. After removal of tetrahydrofuran, the reaction mixture was washed with ethyl acetate/hexane and the crude product was extracted in ethyl acetate. The organic layer was collect and dried over anhydrous Na2SO4, and then the solvent was evaporated. The crude product was washed and purified by crystallization from hot ethanol to afford compound 6. [0072] Yield: 32%. Mp: 202-203° C. (EtOH). 1H-NMR (300 MHz, DMSO-d6): δ ppm 7.10 (d, J=8.7 Hz, 1H, Ar-H5), 7.20 (td, J=9, 2.7 Hz, 1H, Ar-H6′), 7.37 (td, J=11.1, 2.4 Hz, 1H, Ar-H5), 7.49 (d, J=7.8 Hz, 1H, Ar-H6″), 7.57-7.65 (m, 3H, Ar-H3′,4″,5″), 7.95 (d, J=8.1 Hz, 1H, Ar-H6), 8.05 (t, J=1.2 Hz, 1H, Ar-H2), 8.21 (s, 1H, Ar-H2″), 10.66 (s, 1H, NH), 11.70 (s, 1H, OH). HRMS (EI) m/z: calcd [M]+, 393.0788 (C20H12F5NO2+). found, 393.0787.
  • 47
  • [ 455-14-1 ]
  • [ 22494-42-4 ]
  • [ 1468402-84-7 ]
YieldReaction ConditionsOperation in experiment
44% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With thionyl chloride In tetrahydrofuran for 8h; Reflux; Inert atmosphere; Stage #2: 4-trifluoromethylphenylamine In tetrahydrofuran for 14h; 7 Example 7 2′,4′-difluoro-4-hydroxy-N-(4-(trifluoromethyl)phenyl)-[1,1′-biphenyl]-3-carboxamide (compound 7) Example 7 2′,4′-difluoro-4-hydroxy-N-(4-(trifluoromethyl)phenyl)-[1,1′-biphenyl]-3-carboxamide (compound 7) [0073] Thionyl chloride (1 mL, 14 mmol) was added to disfunisal (0.9 g, 4 mmol) in anhydrous tetrahydrofuran (30 mL), and the mixture was refluxed under nitrogen atmosphere for 8 h. After cooling to room temperature, the mixture was steamed to give the intermediate by Dean-Stark apparatus, which residue was used directly in the next step. Freshly prepared intermediate was directly reacted with 4-(trifluoromethyl)aniline (0.5 mL, 4 mmol) in anhydrous tetrahydrofuran (30 mL) for 14 h. After removal of tetrahydrofuran, the reaction mixture was washed with ethyl acetate/hexane and the crude product was extracted in ethyl acetate. The organic layer was collect and dried over anhydrous Na2SO4, and then the solvent was evaporated. The crude product was washed and purified by crystallization from hot ethanol to afford compound 7. [0076] Yield: 44%. Mp: 227-228° C. (EtOH). 1H-NMR (300 MHz, DMSO-d6): δ ppm 7.10 (d, J=8.4 Hz, 1H, Ar-H5), 7.18 (td, J=13.7, 1.5 Hz, 1H, Ar-H6′), 7.36 (td, J=9.3, 2.7 Hz, 1H, Ar-H5′), 7.74 (d, J=9.0 Hz, 2H, Ar-H3″,5″), 7.95 (d, J=8.4 Hz, 2H, Ar-H2″,6″), 8.03 (s, 1H, Ar-H2), 10.67 (s, 1H, NH), 11.66 (s, 1H, OH). HRMS (EI) m/z: calcd [M]+, 393.0788 (C20H12F5NO2+). found, 393.0791.
  • 48
  • [ 22494-42-4 ]
  • [ 54060-30-9 ]
  • [ 1468402-85-8 ]
YieldReaction ConditionsOperation in experiment
38% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With thionyl chloride In tetrahydrofuran for 8h; Reflux; Inert atmosphere; Stage #2: 3-acetylenephenylamine In tetrahydrofuran for 14h; 8 Example 8 N-(3-ethynylphenyl)-2′,4′-difluoro-4-hydroxy-[1,1′-biphenyl]-3-carboxamide (compound 8) Example 8 N-(3-ethynylphenyl)-2′,4′-difluoro-4-hydroxy-[1,1′-biphenyl]-3-carboxamide (compound 8) [0077] Thionyl chloride (1 mL, 14 mmol) was added to disfunisal (0.9 g, 4 mmol) in anhydrous tetrahydrofuran (30 mL), and the mixture was refluxed under nitrogen atmosphere for 8 h. After cooling to room temperature, the mixture was steamed to give the intermediate by Dean-Stark apparatus, which residue was used directly in the next step. Freshly prepared intermediate was directly reacted with 3-ethynylaniline (0.45 mL, 4 mmol) in anhydrous tetrahydrofuran (30 mL) for 14 h. After removal of tetrahydrofuran, the reaction mixture was washed with ethyl acetate/hexane and the crude product was extracted in ethyl acetate. The organic layer was collect and dried over anhydrous Na2SO4, and then the solvent was evaporated. The crude product was washed and purified by crystallization from hot ethanol to afford compound 8. [0080] Yield: 38%. Mp: 215-216° C. (EtOH). 1H-NMR (300 MHz, DMSO-d6): δ ppm 7.09 (d, J=8.7 Hz, 1H, Ar-H5), 7.17-7.26 (m, 2H, Ar-H4″,6′), 7.33-7.41 (m, 2H, Ar-H5′,5″), 7.57-7.65 (m, 2H, Ar-H6,3′), 7.70-7.73 (m, 1H, Ar-H6″), 7.89 (t, J=1.8 Hz, 1H, Ar-H2), 8.05 (t, J=1.2 Hz, 1H, Ar-H2″), 10.48 (s, 1H, NH), 11.79 (s, 1H, OH). HRMS (EI) m/z: calcd [M-H]+, 348.0836 (C21H12F2NO2+). found, 348.0835.
  • 49
  • [ 22494-42-4 ]
  • [ 2237-30-1 ]
  • [ 1468402-86-9 ]
YieldReaction ConditionsOperation in experiment
51% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With thionyl chloride In tetrahydrofuran for 8h; Reflux; Inert atmosphere; Stage #2: m-cyanoaniline In tetrahydrofuran for 14h; 9 Example 9 N-(3-cyanophenyl)-2′,4′-difluoro-4-hydroxy-[1,1′-biphenyl]-3-carboxamide (compound 9) Example 9 N-(3-cyanophenyl)-2′,4′-difluoro-4-hydroxy-[1,1′-biphenyl]-3-carboxamide (compound 9) [0081] Thionyl chloride (1 mL, 14 mmol) was added to disfunisal (0.9 g, 4 mmol) in anhydrous tetrahydrofuran (30 mL), and the mixture was refluxed under nitrogen atmosphere for 8 h. After cooling to room temperature, the mixture was steamed to give the intermediate by Dean-Stark apparatus, which residue was used directly in the next step. Freshly prepared intermediate was directly reacted with 3-aminobenzonitrile (0.47 g, 4 mmol) in anhydrous tetrahydrofuran (30 mL) for 14 h. After removal of tetrahydrofuran, the reaction mixture was washed with ethyl acetate/hexane and the crude product was extracted in ethyl acetate. The organic layer was collect and dried over anhydrous Na2SO4, and then the solvent was evaporated. The crude product was washed and purified by crystallization from hot ethanol to afford compound 9. [0084] Yield: 51%. Mp: 229-230° C. (EtOH). 1H-NMR (300 MHz, DMSO-d6): δ ppm 7.10 (d, J=8.4 Hz, 1H, Ar-H5), 7.16-7.22 (m, 1H, Ar-H6′), 7.35 (td, J=10.35, 2.7 Hz, 1H, Ar-H5′) 7.55-7.63 (m, 4H, Ar-H6,3′,4″,5″), 7.96-8.00 (m, 1H, Ar-H6″), 8.02 (t, J=0.9 Hz, 1H, Ar-H2), 8.21 (t, J=0.9 Hz, 1H, Ar-H2″), 10.63 (s, 1H, NH), 11.66 (s, 1H, OH). HRMS (EI) m/z: calcd [M]+, 350.0867 (C20H12F2N2O2+). found, 350.0857.
  • 50
  • [ 22494-42-4 ]
  • [ 873-74-5 ]
  • [ 1468402-87-0 ]
YieldReaction ConditionsOperation in experiment
54% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With thionyl chloride In tetrahydrofuran for 8h; Reflux; Inert atmosphere; Stage #2: 4-Aminobenzonitrile In tetrahydrofuran for 14h; 10 Example 10 N-(4-cyanophenyl)-2′,4′-difluoro-4-hydroxy-[1,1′-biphenyl]-3-carboxamide (compound 10) Example 10 N-(4-cyanophenyl)-2′,4′-difluoro-4-hydroxy-[1,1′-biphenyl]-3-carboxamide (compound 10) [0085] Thionyl chloride (1 mL, 14 mmol) was added to disfunisal (0.9 g, 4 mmol) in anhydrous tetrahydrofuran (30 mL), and the mixture was refluxed under nitrogen atmosphere for 8 h. After cooling to room temperature, the mixture was steamed to give the intermediate by Dean-Stark apparatus, which residue was used directly in the next step. Freshly prepared intermediate was directly reacted with 4-aminobenzonitrile (0.47 g, 4 mmol) in anhydrous tetrahydrofuran (30 mL) for 14 h. After removal of tetrahydrofuran, the reaction mixture was washed with ethyl acetate/hexane and the crude product was extracted in ethyl acetate. The organic layer was collect and dried over anhydrous Na2SO4, and then the solvent was evaporated. The crude product was washed and purified by crystallization from hot ethanol to afford compound 10. [0088] Yield: 54%. Mp: 189-190° C. (EtOH). 1H-NMR (300 MHz, DMSO-d6): δ ppm 7.19 (td, J=8.4, 0.9 Hz, 1H, Ar-H6′), 7.35 (td, J=10.2, 2.4 Hz, 1H, Ar-H5′), 7.55-7.63 (m, 2H, Ar-H6,3′), 7.81-7.84 (m, 2H, Ar-H3″,5″), 7.91-7.94 (m, 1H, Ar-H2″,6″), 7.98 (t, J=1.2 Hz, 1H, Ar-H2), 10.70 (s, 1H, NH), 11.55 (s, 1H, OH). HRMS (EI) m/z: calcd [M]+, 350.0867 (C20H12F2N2O2+). found, 350.0872.
  • 51
  • [ 22494-42-4 ]
  • [ 6315-89-5 ]
  • [ 1468402-88-1 ]
YieldReaction ConditionsOperation in experiment
34% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With thionyl chloride In tetrahydrofuran for 8h; Reflux; Inert atmosphere; Stage #2: 3,4-dimethoxyaniline In tetrahydrofuran for 14h; 11 Example 11 N-(3,4-dimethoxyphenyl)-2′,4′-difluoro-4-hydroxy-[1,1′-biphenyl]-3-carboxamid (compound 11) Example 11 N-(3,4-dimethoxyphenyl)-2′,4′-difluoro-4-hydroxy-[1,1′-biphenyl]-3-carboxamid (compound 11) [0089] Thionyl chloride (1 mL, 14 mmol) was added to disfunisal (0.9 g, 4 mmol) in anhydrous tetrahydrofuran (30 mL), and the mixture was refluxed under nitrogen atmosphere for 8 h. After cooling to room temperature, the mixture was steamed to give the intermediate by Dean-Stark apparatus, which residue was used directly in the next step. Freshly prepared intermediate was directly reacted with 3,4-dimethoxyaniline (0.61 g, 4 mmol) in anhydrous tetrahydrofuran (30 mL) for 14 h. After removal of tetrahydrofuran, the reaction mixture was washed with ethyl acetate/hexane and the crude product was extracted in ethyl acetate. The organic layer was collect and dried over anhydrous Na2SO4, and then the solvent was evaporated. The crude product was washed and purified by crystallization from hot ethanol to afford compound 11. [0092] Yield: 34%. Mp: 186-187° C. (EtOH). 1H-NMR (300 MHz, DMSO-d6): δ ppm 3.75 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 6.95 (d, J=9 Hz, 1H, Ar-H2″), 7.07 (d, J=6.6 Hz, 1H; Ar-H5), 7.17-7.25 (m, 2H, Ar-H6′,5″), 7.31-7.39 (m, 2H, Ar-H5′,6″), 7.56-7.66 (m, 2H, Ar-H6,3′), 8.11 (s, 1H, Ar-H2), 10.33 (s, 1H, NH), 12.12 (s, 1H, OH). HRMS (EI) m/z: calcd [M]+, 385.1126 (C21H17F2NO4+). found, 385.1124.
  • 52
  • [ 22494-42-4 ]
  • [ 536-90-3 ]
  • [ 1468402-89-2 ]
YieldReaction ConditionsOperation in experiment
32% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With thionyl chloride In tetrahydrofuran for 8h; Reflux; Inert atmosphere; Stage #2: m-Anisidine In tetrahydrofuran for 14h; 12 Example 12 2′,4′-difluoro-4-hydroxy-N-(3-methoxyphenyl)-[1,1′-biphenyl]-3-carboxamide (compound 12) Example 12 2′,4′-difluoro-4-hydroxy-N-(3-methoxyphenyl)-[1,1′-biphenyl]-3-carboxamide (compound 12) [0093] Thionyl chloride (1 mL, 14 mmol) was added to disfunisal (0.9 g, 4 mmol) in anhydrous tetrahydrofuran (30 mL), and the mixture was refluxed under nitrogen atmosphere for 8 h. After cooling to room temperature, the mixture was steamed to give the intermediate by Dean-Stark apparatus, which residue was used directly in the next step. Freshly prepared intermediate was directly reacted with 3-methoxyaniline (0.46 g, 4 mmol) in anhydrous tetrahydrofuran (30 mL) for 14 h. After removal of tetrahydrofuran, the reaction mixture was washed with ethyl acetate/hexane and the crude product was extracted in ethyl acetate. The organic layer was collect and dried over anhydrous Na2SO4, and then the solvent was evaporated. The crude product was washed and purified by crystallization from hot ethanol to afford compound 12. [0096] Yield: 32%. Mp: 187-188° C. (EtOH). 1H-NMR (300 MHz, DMSO-d6): δ ppm 3.76 (s, 3H, OCH3), 6.70-6.74 (m, 1H, Ar-H5), 7.08 (d, J=8.4 Hz, 1H, Ar-H5), 7.16-7.39 (m, 4H, Ar-H6′,2″,4″,6″), 7.57-7.65 (m, 2H, Ar-H6,3′), 8.07 (s, 1H, Ar-H2), 10.39 (s, 1H, NH), 11.90 (s, 1H, OH). HRMS (EI) m/z: calcd [M]+, 355.1020 (C20H15F2NO3+). found, 355.1014.
  • 53
  • [ 57946-56-2 ]
  • [ 22494-42-4 ]
  • [ 1468402-79-0 ]
YieldReaction ConditionsOperation in experiment
30% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With thionyl chloride In tetrahydrofuran for 8h; Reflux; Inert atmosphere; Stage #2: 2-fluoro-4-chloroaniline In tetrahydrofuran for 14h; 1 N-(4-chloro-2-fluorophenyl)-2',4'-difluoro-4-hydroxybiphenyl-3-carboxamide (compound 1) Thionyl chloride (1 mL, 14 mmol) was added to disfunisal (0.9 g, 4 mmol) in anhydrous tetrahydrofuran (30 mL), and the mixture was refluxed under nitrogen atmosphere for 8 h. After cooling to room temperature, the mixture was steamed to give the intermediate by Dean-Stark apparatus, which residue was used directly in the next step. Freshly prepared intermediate was directly reacted with 4-chloro-2-fluoroaniline (0.5 mL, 4 mmol) in anhydrous tetrahydrofuran (30 mL) for 14 h. After removal of tetrahydrofuran, the reaction mixture was washed with ethyl acetate/hexane and the crude product was extracted in ethyl acetate. The organic layer was collect and dried over anhydrous Na2SO4, and then the solvent was evaporated. The crude product was washed and purified by crystallization from hot ethanol to afford compound 1. Yield: 30%. Mp: 245-246° C. (EtOH). 1H-NMR (300 MHz, DMSO-d6): δ ppm 7.12 (d, J=6.0 Hz, 1H, Ar-H5), 7.19 (td, J=9.0, 1.8 Hz, 1H, Ar-H6'), 7.31-7.40 (m, 2H, Ar-H5,6"), 7.55-7.64 (m, 3H, Ar-H6,3',5"), 8.14 (t, J=1.5 Hz, 1H, Ar-H2), 8.24 (t, J=8.7 Hz, 1H, Ar-H3"), 10.77 (s, 1H, NH), 12.19 (s, 1H, OH). HRMS (EI) m/z: calcd [M]+, 377.0430 (C19H11ClF3NO2+). found, 377.33.
  • 54
  • [ 866625-02-7 ]
  • [ 22494-42-4 ]
  • 55
  • [ 528-43-8 ]
  • [ 22494-42-4 ]
  • 5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl-bis(2',4'-difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylate) [ No CAS ]
  • 56
  • [ 528-43-8 ]
  • [ 22494-42-4 ]
  • 5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl-2',4'-difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylate [ No CAS ]
  • 57
  • [ 22494-42-4 ]
  • [ 10050-08-5 ]
  • tris-o-tolylbismuth bis(2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate) [ No CAS ]
YieldReaction ConditionsOperation in experiment
75.1% With dihydrogen peroxide In diethyl ether; water at 20℃;
  • 58
  • 2',4'-difluoro-4-hydroxy-N-(quinolin-8-yl)-[1,1'-biphenyl]-3-carboxamide [ No CAS ]
  • [ 22494-42-4 ]
YieldReaction ConditionsOperation in experiment
88% With hydrogenchloride In water at 110℃; for 24h; Inert atmosphere;
  • 59
  • [ 22494-42-4 ]
  • [ 102-92-1 ]
  • O-cinnamoyl-2,4-difluorobenzenesalicylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
86.4% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With pyridine In tetrahydrofuran at 20℃; for 0.5h; Stage #2: cinnamoyl chloride In tetrahydrofuran at 20℃; Cooling with ice; 1 Example 1: synthesis prepartion of O-cinnamoyl-2,4-difluorobenzenesalicylic acid(V) Was added to the other reaction flask25.0 g (0.10 mol) of diflunisal, 60 ml of THF, 9.6 g (0.12 mol) of pyridine,Stirring at room temperature for 30min,The cinnamoyl chloride solution obtained in the previous step was slowly added under ice-cooling, and the mixture was stirred at room temperature overnight.Filtration,To the filtrate was added 200 ml (1 mol / l) dilute hydrochloric acid,Stirring, precipitation of light yellow solid; filter, filter cake washed with ethanol, dry,That is, O-cinnamoyl-2,4-difluorobenzenesalicylic acid crude (V), Yield: 86.4%
Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With pyridine In tetrahydrofuran at 20℃; for 0.5h; Stage #2: cinnamoyl chloride In tetrahydrofuran at 20℃; 1 preparation O-cinnamoyl-fluorobenzene salicyate (V) synthesis of To join another reaction bottle 25.0g (0.10mol) diflunisal, 60ml of THF, 9.6g (0.12mol) of pyridine, stirring at room temperature for 30 min, under in ice-bath slowly adding one step on the prepared cinnamic acid chloride solution, stirring at room temperature overnight. Filtering, the filtrate is added in 200 ml (1mol/L) dilute hydrochloric acid, stirring, precipitated strawcoloured solid; filtering, the filter cake is washed with ethanol washing, drying, to obtain the O-cinnamoyl-fluorobenzene salicylic acid crude product (V), yield: 86.4%, melting point: 192-195° C (uncorrected).
Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With pyridine In tetrahydrofuran at 20℃; for 0.5h; Stage #2: cinnamoyl chloride In tetrahydrofuran at 20℃; 1 Preparation of 0-cinnamoyl-fluorophenylsalicylic acid (V) To the reaction flask (0.12 mol) of pyridine, stirring at room temperature for 30 min, slowly add the cinnamon obtained in the previous step in an ice bath. The acid chloride solution stirringat room temperature for overnight. Filtration, to the filtrate add 200ml (1mol/ L) dilute hydrochloric acid and stirring to precipitate a light yellow solid;filtering and filtering the cake with ethanol and drying to obtain crudeo-cinnamoyl-fluorobenzalicylic acid (V) : 86.4%, m.p. 192-195 ° C(uncorrected).
Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With pyridine at 20℃; for 0.5h; Stage #2: cinnamoyl chloride at 20℃; Cooling with ice; 1 Preparation of 0-cinnamoyl-fluorophenylsalicylic acid (V) To another reaction flask was added 25. 0 g (0.10 mol) of diflunisal, (0.12 mol) of pyridine, stirred at room temperature for 30 min, The cinnamoyl chloride solution obtained in the previous step was slowly added under ice-cooling, Stirring at room temperature overnight. The filter cake washed with ethanol and dried, that is, o-cinnamoyl-fluorobenzene salicylic acid crude (V), the concentration of hydrochloric acid, , Yield: 86.4%, m.p .: 192-195 ° C (uncol positive).

  • 60
  • [ 67-56-1 ]
  • cobalt(II) chloride hexahydrate [ No CAS ]
  • [ 22494-42-4 ]
  • [Co(diflunisal)2(methanol)4] [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% Stage #1: methanol; 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With potassium hydroxide for 1h; Stage #2: cobalt(II) chloride hexahydrate for 0.5h; 2.1 2.2.1. Synthesis of complexes 1-3, [Co(L)2(MeOH)4] (HL = Hdifl, Hnif,Hfluf) General procedure: A methanolic solution (15mL) containing the NSAID (HL=Hdifl, Hnif, Hfluf) (0.4mmol) and KOH (0.4mmol, 23 mg) was stirred for 1h. The solution was added to a methanolic solution (10mL) of CoCl2·6H2O (0.2mmol, 47mg) and the reaction mixture was stirred for 0.5h. The reaction solution was filtered and left for slow evaporation. [Co(difl-O)2(MeOH)4], 1: Hdifl (0.4mmol, 101mg) was used as the NSAID. Violet crystals of [Co(difl)2(MeOH)4], 1 (90mg, 65 %) suitable for X-ray structure determination, were deposited after slow evaporation of the mother solution for two weeks. Anal. Calcd. for C30H30CoF4O10 (MW=685.47) C, 52.56; H, 4.41; found: C, 52.43; H, 3.95%. IR (KBr disk): νmax, cm-1; ν asym(CO2), 1609(vs (very strong)); νsym(CO2), 1406 (vs); Δν(CO2)=νasym(CO2)-νsym(CO2): 203 cm-1; UV-vis: λ, nm (ε, M-1 cm-1) as nujol mull: 690, 538, 466, 346, 299; in DMSO: 700 (40), 547 (80), 468 (160), 340 (5060), 295 (9100). μeff at room temperature=4.20 BM. Soluble in DMSO (ΛM=7Scm2mol-1, in 1mM DMSO solution).
  • 61
  • [ 67-56-1 ]
  • [ 366-18-7 ]
  • cobalt(II) chloride hexahydrate [ No CAS ]
  • [ 22494-42-4 ]
  • [Co(diflunisal)2(2,2′-bipyridine)(methanol)2] [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% Stage #1: methanol; 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With potassium hydroxide for 1h; Stage #2: [2,2]bipyridinyl; cobalt(II) chloride hexahydrate for 0.5h; 2.2.3. Synthesis of complexes 6-9 General procedure: The NSAID (HL=Hfluf, Hdifl) (0.5mmol) was dissolved in MeOH (15mL) and was deprotonated with KOH (0.5mmol, 28mg) after 1h stirring. This solution was added dropwise and simultaneously with a methanolic solution (5mL) containing bipy or phen (0.25mmol) into a solution of CoCl2·6H2O (0.25mmol, 59mg) in MeOH (5mL). The resultant mixture was stirred for 30min and left for slow evaporation.
  • 62
  • [ 67-56-1 ]
  • [ 66-71-7 ]
  • cobalt(II) chloride hexahydrate [ No CAS ]
  • [ 22494-42-4 ]
  • [Co(diflunisal)2(1,10-phenanthroline)(methanol)2] [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% Stage #1: methanol; 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With potassium hydroxide for 1h; Stage #2: 1,10-Phenanthroline; cobalt(II) chloride hexahydrate for 0.5h; 2.2.3. Synthesis of complexes 6-9 General procedure: The NSAID (HL=Hfluf, Hdifl) (0.5mmol) was dissolved in MeOH (15mL) and was deprotonated with KOH (0.5mmol, 28mg) after 1h stirring. This solution was added dropwise and simultaneously with a methanolic solution (5mL) containing bipy or phen (0.25mmol) into a solution of CoCl2·6H2O (0.25mmol, 59mg) in MeOH (5mL). The resultant mixture was stirred for 30min and left for slow evaporation.
  • 63
  • [ 3081-61-6 ]
  • [ 22494-42-4 ]
  • L-theanine diflunisal cocrystal [ No CAS ]
YieldReaction ConditionsOperation in experiment
In water; isopropyl alcohol; 0.373 g of diflunisal (1 .491 mmol) and 0.269 g of L-<strong>[3081-61-6]theanine</strong> (1 .544 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 10a, while the FTIR spectrum is shown in Figure 10b. The DSC melting endotherm of the product was characterized by a peak maximum at 172C.
  • 64
  • [ 67-56-1 ]
  • [ 1562-95-4 ]
  • nickel(II) chloride hexahydrate [ No CAS ]
  • [ 22494-42-4 ]
  • C48H32F4N6NiO8 [ No CAS ]
YieldReaction ConditionsOperation in experiment
63% Stage #1: methanol; 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With potassium hydroxide at 20℃; for 1h; Stage #2: di-2-pyridyl ketone oxime; nickel(II) chloride hexahydrate at 20℃; for 0.5h; 2.2.2. Synthesis of [Ni(difl-O)2(Hpko-N,N′)2], 2 A methanolic solution (10 mL) containing Hdifl (0.4mmol, 100 mg)and KOH (0.4 mmol, 23 mg) was stirred for 1 h at room temperature.The resultant solution was added simultaneously with a methanolic solution (5 mL) of Hpko (0.4 mmol, 79 mg) to a methanolic solution(5 mL) of NiCl2·6H2O (0.2 mmol, 48 mg). The solution was stirred for30 min and left for slowevaporation at roomtemperature. Blue crystalsof [Ni(difl)2(Hpko)2], 2 (190 mg, 63%), suitable for X-ray structure determination,were collected after a week. Anal. Calcd. forC48H27F4N6NiO8 (MW = 955.22) C, 60.34; H, 3.34; N, 8.79%; found: C,60.10; H, 3.42; N, 8.65%. IR (KBr disk): νmax, cm-1; ν asym(CO2),1575(vs); νsym(CO2), 1374(s); Δν (CO2) = 201 cm-1; ρ(CH)Hpko:775 (medium (m)); UV-vis: λ, nm (ε, M-1 cm-1) as nujol mull:970(sh), 635, 422(sh), 315(sh); in DMSO: 1000 (15), 630(sh) (18),455(sh) (40), 310(sh) (12,500); 10Dq = 10,000 cm-1, B =493 cm-1, 10Dq/B=19.1. μeff at roomtemperature=3.35 BM. Solublein acetonitrile, chloroform, DMSO (ΛM=9Scm2 mol-1, in1mMDMSOsolution) and DMF.
  • 65
  • [ 67-56-1 ]
  • [ 66-71-7 ]
  • nickel(II) chloride hexahydrate [ No CAS ]
  • [ 22494-42-4 ]
  • C40H30F4N2NiO8 [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% Stage #1: methanol; 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With potassium hydroxide at 20℃; for 1h; Stage #2: 1,10-Phenanthroline; nickel(II) chloride hexahydrate at 20℃; for 0.5h; 2.2.3. Synthesis of complexes 3-5 General procedure: A methanolic solution (10 mL) containing Hdifl (0.4mmol, 100 mg)and KOH (0.4 mmol, 23 mg) was stirred for 1 h at room temperature.The resultant solution was added simultaneously with a methanolic solution (5 mL) of Hpko (0.4 mmol, 79 mg) to a methanolic solution(5 mL) of NiCl2·6H2O (0.2 mmol, 48 mg). The solution was stirred for30 min and left for slowevaporation at roomtemperature. Blue crystalsof [Ni(difl)2(Hpko)2], 2 (190 mg, 63%), suitable for X-ray structure determination,were collected after a week. Anal. Calcd. forC48H27F4N6NiO8 (MW = 955.22) C, 60.34; H, 3.34; N, 8.79%; found: C,60.10; H, 3.42; N, 8.65%. IR (KBr disk): νmax, cm-1; ν asym(CO2),1575(vs); νsym(CO2), 1374(s); Δν (CO2) = 201 cm-1; ρ(CH)Hpko:775 (medium (m)); UV-vis: λ, nm (ε, M-1 cm-1) as nujol mull:970(sh), 635, 422(sh), 315(sh); in DMSO: 1000 (15), 630(sh) (18),455(sh) (40), 310(sh) (12,500); 10Dq = 10,000 cm-1, B =493 cm-1, 10Dq/B=19.1. μeff at roomtemperature=3.35 BM. Solublein acetonitrile, chloroform, DMSO (ΛM=9Scm2 mol-1, in1mMDMSOsolution) and DMF.
  • 66
  • [ 67-56-1 ]
  • [ 366-18-7 ]
  • nickel(II) chloride hexahydrate [ No CAS ]
  • [ 22494-42-4 ]
  • C38H30F4N2NiO8 [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% Stage #1: methanol; 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With potassium hydroxide at 20℃; for 1h; Stage #2: [2,2]bipyridinyl; nickel(II) chloride hexahydrate at 20℃; for 0.5h; 2.2.3. Synthesis of complexes 3-5 General procedure: A methanolic solution (10 mL) containing Hdifl (0.4mmol, 100 mg)and KOH (0.4 mmol, 23 mg) was stirred for 1 h at room temperature.The resultant solution was added simultaneously with a methanolic solution (5 mL) of Hpko (0.4 mmol, 79 mg) to a methanolic solution(5 mL) of NiCl2·6H2O (0.2 mmol, 48 mg). The solution was stirred for30 min and left for slowevaporation at roomtemperature. Blue crystalsof [Ni(difl)2(Hpko)2], 2 (190 mg, 63%), suitable for X-ray structure determination,were collected after a week. Anal. Calcd. forC48H27F4N6NiO8 (MW = 955.22) C, 60.34; H, 3.34; N, 8.79%; found: C,60.10; H, 3.42; N, 8.65%. IR (KBr disk): νmax, cm-1; ν asym(CO2),1575(vs); νsym(CO2), 1374(s); Δν (CO2) = 201 cm-1; ρ(CH)Hpko:775 (medium (m)); UV-vis: λ, nm (ε, M-1 cm-1) as nujol mull:970(sh), 635, 422(sh), 315(sh); in DMSO: 1000 (15), 630(sh) (18),455(sh) (40), 310(sh) (12,500); 10Dq = 10,000 cm-1, B =493 cm-1, 10Dq/B=19.1. μeff at roomtemperature=3.35 BM. Solublein acetonitrile, chloroform, DMSO (ΛM=9Scm2 mol-1, in1mMDMSOsolution) and DMF.
  • 67
  • [ 67-56-1 ]
  • [ 1202-34-2 ]
  • nickel(II) chloride hexahydrate [ No CAS ]
  • [ 22494-42-4 ]
  • C36H23F4N3NiO6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% Stage #1: methanol; 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With potassium hydroxide at 20℃; for 1h; Stage #2: di(pyridin-2-yl)amine; nickel(II) chloride hexahydrate at 20℃; for 0.5h; 2.2.3. Synthesis of complexes 3-5 General procedure: A methanolic solution (10 mL) containing Hdifl (0.4mmol, 100 mg)and KOH (0.4 mmol, 23 mg) was stirred for 1 h at room temperature.The resultant solution was added simultaneously with a methanolic solution (5 mL) of Hpko (0.4 mmol, 79 mg) to a methanolic solution(5 mL) of NiCl2·6H2O (0.2 mmol, 48 mg). The solution was stirred for30 min and left for slowevaporation at roomtemperature. Blue crystalsof [Ni(difl)2(Hpko)2], 2 (190 mg, 63%), suitable for X-ray structure determination,were collected after a week. Anal. Calcd. forC48H27F4N6NiO8 (MW = 955.22) C, 60.34; H, 3.34; N, 8.79%; found: C,60.10; H, 3.42; N, 8.65%. IR (KBr disk): νmax, cm-1; ν asym(CO2),1575(vs); νsym(CO2), 1374(s); Δν (CO2) = 201 cm-1; ρ(CH)Hpko:775 (medium (m)); UV-vis: λ, nm (ε, M-1 cm-1) as nujol mull:970(sh), 635, 422(sh), 315(sh); in DMSO: 1000 (15), 630(sh) (18),455(sh) (40), 310(sh) (12,500); 10Dq = 10,000 cm-1, B =493 cm-1, 10Dq/B=19.1. μeff at roomtemperature=3.35 BM. Solublein acetonitrile, chloroform, DMSO (ΛM=9Scm2 mol-1, in1mMDMSOsolution) and DMF.
  • 68
  • [ 67-56-1 ]
  • nickel(II) chloride hexahydrate [ No CAS ]
  • [ 22494-42-4 ]
  • C30H30F4NiO10 [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% Stage #1: methanol; 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With potassium hydroxide for 1h; Stage #2: nickel(II) chloride hexahydrate for 0.5h; 2.2.1. Synthesis of [Ni(difl-O)2(MeOH)4], 1 A methanolic solution (15 mL) containing Hdifl (0.4mmol, 100 mg)and KOH (0.4mmol, 23 mg)was stirred for 1 h. The solution was addedto a methanolic solution (5 mL) of NiCl2·6H2O (0.2 mmol, 47 mg) andthe reaction mixture was stirred for 30 min. The reaction solution wasfiltered and left for slow evaporation. Green crystals of[Ni(difl)2(MeOH)4], 1 (70 mg, 55%) were collected after five days.Anal. Calcd. for C30H30NiO10F4 (MW = 685.27) C, 52.58; H, 4.41%;found: C, 52.53; H, 4.58%. IR (KBr disk): νmax, cm-1; νasym(CO2),1566(very strong (vs)); νsym(CO2), 1357(strong(s)); Δν(CO2) =νasym(CO2) - νasym(CO2) = 209 cm-1; UV-vis: λ, nm(ε, M-1 cm-1)as nujol mull: 990(shoulder (sh)), 665, 411(sh), 305(sh); in DMSO:990 (10), 680 (15), 419 (50), 311(sh) (8000); 10Dq = 10,101 cm-1,B = 551 cm-1, 10Dq/B = 18.3. μeff at room temperature = 3.08 BM.Soluble in acetonitrile, acetone, DMSO (ΛM = 11 S cm2 mol-1, in1 mM DMSO solution) and DMF
  • 69
  • [ 22494-42-4 ]
  • C8H6Cl2FNO2 [ No CAS ]
  • C21H13ClF3NO5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With pyridine In tetrahydrofuran at 20℃; for 0.5h; Stage #2: C8H6Cl2FNO2 In tetrahydrofuran at 20℃; Cooling with ice; 1 Example 1: Preparation of 6-ethoxy fluorochlorizin fluoride Benzene salicylic acid (IV) 10.0 g (0.04 mol) of diflunisal, 60mL THF, 3.8 g (0.048 mol) of pyridine was added to the reaction flask, Stirring at room temperature for 0.5h. Ice bath slowly dropping fumaric acid chloride-THF solution, Stir at room temperature overnight. Filter, The solvent is distilled off, Stirring with anhydrous ethanol, Filter, dry, 6-ethoxy fluorochlorizin fluoride benzene salicylic acid crude (IV), Yield: 72.9%
  • 70
  • [ 22494-42-4 ]
  • C8H7ClFNO3 [ No CAS ]
  • C21H13ClF3NO5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: C8H7ClFNO3 With thionyl chloride In N,N-dimethyl-formamide; toluene at 70℃; for 6h; Stage #2: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With pyridine In tetrahydrofuran at 20℃; for 0.5h; Stage #3: In tetrahydrofuran at 20℃; 1 Example 1: Preparation6-ethoxy fluorochlorideNicotinic acidFluorobenzene salicylic acid(IV) A solution of 10.5 g (0.048 mol) of fluorochlorinic acid (VII), 11.4 g (0.096 mol) of SOCl2, 100 mL of toluene and 10 drops of DMF was added to the reaction flask and reacted at 70C for 6 hours. Cooled, filtered, and the solvent evaporated to give an oily liquid which was dissolved in 20 mL of THF and allowed to stand.10.0 g (0.04 mol)Difluoronil, 60 mL THF, 3.8 g (0.048 mol) of pyridine were added to the reaction flask,Stirring at room temperature for 0.5h.Slowly dripping under ice bathFluorochloroyl chloride-THF solution was added at room temperature overnight.Filtration, evaporation of the solvent, stirring with anhydrous ethanol, suction, drying, 6-ethoxy fluoro-nicotinamide fluoride Acid crude (IV), yield: 72.9%, melting point: 191-192 ° C (uncorrected).
  • 71
  • [ 865321-51-3 ]
  • [ 22494-42-4 ]
  • C19H16F2N2O3Pt [ No CAS ]
YieldReaction ConditionsOperation in experiment
53% With sodium carbonate; silver nitrate In N,N-dimethyl-formamide at 20℃; for 24h; Darkness; 7 Picoplatin (188 mg),AgN03 (170 mg),Diflunisal(125 mg) and Na2C03 (35.3 mg)Add to a round-bottomed flask, then add 15ml of DMF, dark at room temperature for 24h.The precipitate was removed by centrifugation. After the filtrate was concentrated, 50 ml of ethyl acetate was added and the mixture was washed three times with 50 ml of 0.1 M Na2CO3 and washed with water three times. The ethyl acetate layer was collected and dried over anhydrous sodium sulfate overnight.Filtration, the filtrate with methanol: dichloromethane = 1: 9 eluent, silica gel column chromatography to obtain the diflunisal - picoplatin complex, a yield of 53%, the formula is shown in the formula 6.
  • 72
  • [ 22494-42-4 ]
  • [ 41904-39-6 ]
  • C21H14F2O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
In N,N-dimethyl-formamide; benzene at 65℃; for 8h; 1.2 step 1, 1 g of Ruthenium trichloride hydrate and 30mL of g-terpinene are dissolved in 70mL of absolute ethanol, heated to reflux for 6 hours, standing precipitation and then obtained Dichloro-dichloride-Bis-cymene di-ruthenium; step 2, Dissolve 8 g of Diflunisal into 40mL of solvent, add 4 g of the catalyst to N, N-dimethylformamide, and then added the substituted phenylacetyl chloride, the reaction is carried out at 65 ° C for 8 hours, after removing the solvent, and then obtained Phenylacetyl fluorobenzene Salicylic acid; step 3, 1g of Dichloro-dichloride-Bis-cymene di-ruthenium and 3g of Phenylacetyl fluorobenzene Salicylic acid are dissolved in 80mL of tetrahydrofuran, carry on reaction at 65 ° C for 6 hours, purified, that is, too. among them, in the first step Hydrated ruthenium trichloride as Ruthenium content of 45% by weight of hydrated ruthenium trichloride; the purity of g-terpinene is 70%. among them, in the second step the solvent is benzene. among them, in the second step the solvent is removed by distillation under reduced pressure, the use of circulating pump pressure in the rotary evaporator decompression operation, it is easy to remove, pressure set at 20-40mmHg. among them, in the third step the purification steps are: in the step third after completion of the reaction the solvent is evaporated, add the hydrochloric acid immersion with 10% of mass fraction, stirring until crystallization, washed with ethanol solution 3-5 times, it can be dry.
  • 73
  • [ 321-14-2 ]
  • [ 144025-03-6 ]
  • [ 22494-42-4 ]
YieldReaction ConditionsOperation in experiment
95% With bis(di-tert-​butyl(4-​dimethylaminophenyl)​phosphine)​dichloropalladium(II); tetrabutylammomium bromide; potassium carbonate In ethanol; water for 8h; Inert atmosphere; Reflux; 4 Example 4: The molar ratio of 2,4-difluorophenylboronic acid to 5-chlorosalicylic acid is 1:0.8.Tetrabutylammonium bromide as a phase transfer catalyst,The palladium catalyst is PdCl2(Amphos)2500ml three bottle,After replacing the air with nitrogen,Added 31.6 g (0.2 mol) of 2,4-difluorophenylboronic acid,5-chlorosalicylic acid 27.6g (0.16mol), 200ml of ethanol,A solution of 69g (0.5mol) of potassium carbonate dissolved in 210ml of water was slowly added.Tetrabutylammonium bromide 13g (0.04 mol) was added under a nitrogen atmosphere.PdCl 2 (Amphos) 2 catalyst 280 mg (0.2 mol %).After mixing, heat to reflux,Stir the reaction for 8h under reflux and complete the reaction.After the reaction is completed,Cool down to below 30°C,The pH is carefully adjusted to 3 or less with concentrated hydrochloric acid at a temperature not exceeding 40°C.Add 200ml of water and distill out ethanolCool down to room temperatureFiltration gave an off-white solid. After washing, drying and recrystallization with 25% ethanol,White diflunisal product with a yield of 38 gThe yield was calculated as 95% with 5-chlorosalicylic acid.
  • 74
  • [ 108-73-6 ]
  • [ 22494-42-4 ]
  • 7-(2,4-difluorophenyl)-1,3-dihydroxy-9H-xanthen-9-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% With methanesulfonic acid; phosphorus pentoxide at 90℃; for 0.333333h; 1 Synthesis of 7-(2,4-difluorophenyl)-1,3-dihydroxyxanthone issolve 0.68 g of phosphorus pentoxide (4.8 mmol) and 15 mL of methane sulfonic acid (MeSO3H) in a 50 mL round-bottom flask, heat to 110°C, and stir to dissolve. Then, the reaction solution is reduced to 90°C, and 0.40 is added in order. g 5-(2,4-Difluorophenyl)-2-hydroxybenzoic acid (1.6 mmol) and 0.20 g of phloroglucin (1.6 mmol) were reacted at 90°C for 20 min.The reaction solution waspoured into water and the solid precipitated, which was filtered under suction and air-dried. The initial product waspressed witha mixed solvent of ethyl acetate and petroleum ether (VEtOAc:VPetroleum ether= 1:10) over 200-300 mesh. Silica gel column gave 0.41 g of a yellow solid with a yield of 76.0%.
76% With Eaton’s reagent at 90℃; for 0.333333h; General procedure for preparation of substituted 1,3-dihydroxy-9H-xanthones General procedure: A mixture of phosphorus pentoxide (0.5 g) and methanesulfonic acid (10 ml) was heated at110 °C until a clear solution was obtained. The solution was then lowered to 90 °C. A mixtureof phloroglucinol (0.2 g, 1.6 mmol) and the relevant substituted salicylic acid (1.6 mmol)were added to this solution. Heating was continued for 20 min, and the reaction mixturewas poured into ice-water. The resulting solid was collected by filtration, washed with water,dried, and purified by flash column chromatography to afford the target xanthone.
  • 75
  • [ 119-30-2 ]
  • [ 144025-03-6 ]
  • [ 22494-42-4 ]
YieldReaction ConditionsOperation in experiment
98% With C32H26Cl2N8O4Pd2; potassium carbonate In methanol; lithium hydroxide monohydrate for 0.0833333h; Reflux;
98% With potassium carbonate In lithium hydroxide monohydrate for 0.0833333h; Reflux; Suzuki reaction catalyzed by Pd-M(Ni,Co,Fe,Cu) - Pro/Al2O3 composites (general procedure) General procedure: To a mixture of 1.20 mmol of arylboronic acid, 1.00 mmol of aryl bromide, and 0.35 g (2.50 mmol) of K2CO3 in 5 mL of H2O (or 50% aqueous methanol) was added a catalyst (10 mg 1-4, 6, 3.3 mg 5, 0.1 mol % Pd). The reactor was placed in a silicon bath preheated to 120°C (for reactions in aqueous methanol) or to 160°C (for reactions in water), the reaction mixture was intensively stirred for 15-20 min at reflux (yields of the cross-coupling product are given in Table 1). The reactions progress was monitored by TLC (eluent hexane-Et2O, 3 : 1) using calibration solutions of the corresponding biaryl and aryl bromide (at a molar ratio of 1 : 1 and 9 : 1). After the reaction completion, the catalyst was separated by centrifugation (3000 rpm)and, after washing with water and ethanol, was reused. The centrifugate was diluted with water, filtered, 10- 15 vol % ethanol was added, heated to ~50°C, and slowly acidified with 5% HCl to pH 2-3 with stirring. As a result, well filterable precipitates were formed, and analytically pure samples of the cross-coupling product were obtained without the use of chromatographic methods. Yields in exp. 1, 4, 10 (Table 1) were also determined by 1H NMR using tetrachloroethane (0.5 mmol) as an internal standard.
52% With trimethyl-(2-hydroxyethyl)ammonium chloride; palladium diacetate; anhydrous sodium carbonate; propane-1,2,3-triol at 60℃; for 5h;
  • 76
  • C10 bis-L-lactate diol [ No CAS ]
  • [ 846588-02-1 ]
  • [ 22494-42-4 ]
  • None [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: C10 bis-L-lactate diol; diflunisal-C12-diflunisal diacid chloride With triethylamine In tetrahydrofuran at 30℃; for 12h; Stage #2: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With triethylamine In chloroform at 0℃; for 1h; Stage #3: With triethylamine; trichloroacetic acid anhydride In dichloromethane; chloroform at 0℃; for 1h; 37 Example 37: Preparation of Random Poly (DF-C12-DF co-Diflunisal) Anhydride (Compound 28a) [0154] A solution of 2.755 g C10-bis-L-lactate diol (Compound 19b) and 3.623 ml anhydrous TEA in 25 ml anhydrous THF was added to 19.00 g of a solution of DF-C12-DF diacid chloride (Compound 15c) in 125 ml anhydrous THF. The reaction mixture was stirred for 12 hours at 30°C, concentrated in vacuo, co-evaporated twice with 200 ml additional chloroform, and dried in a vacuum oven at 30°C overnight. The dried intermediate (pre-polymer) was re-dissolved in 100 ml anhydrous chloroform, and was cooled to 0°C in an ice bath. A mixture of 3.466 g DF and 4.058 ml anhydrous TEA was made in 100 ml anhydrous chloroform, and was slowly added to the pre-polymer solution at 0°C. The reaction mixture was stirred for 1 hour at 0°C, washed with 200 ml IN HC1 and 200 ml distilled water, dried over anhydrous magnesium sulfate, concentrated in vacuo, and dried in a vacuum oven at 40°C overnight. 0.317 ml anhydrous TEA were added to a solution of 21.6 g intermediate prepolymer in 140 ml DCM, and a solution of 111 mg triphosgene in 5.0 ml anhydrous chloroform was added drop-wise at 0°C. The reaction mixture was stirred at 0°C for 1 hour, diluted with 40 ml chloroform, washed with 100 ml IN HC1 and twice with 500 ml distilled water, and dried over anhydrous MgSO4. The solution was concentrated in vacuo to about 50 ml, and poured into anhydrous diethyl ether in a Teflon cylinder with stirring to precipitate the product. The supernate was decanted, and the solid was washed with ethyl ether, and dried in a vacuum oven at 40°C overnight to yield 13.3 g of product. MW=120,000 ; PDI=1.35
  • 77
  • [ 846588-04-3 ]
  • [ 34959-19-8 ]
  • [ 22494-42-4 ]
  • None [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: diflunisal-C14-diflunisal diacid chloride; 1,16-hexadecanedioyl dichloride; 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid In chloroform at 0℃; for 1h; Stage #2: With triethylamine In chloroform at 0℃; for 1h; Stage #3: With trichloroacetic acid anhydride In chloroform at 0℃; for 1h; 32 Example 32: Preparation of Random Poly Diflunisal-C14-Diflunisal-co DF Anhydride (DF-C14-DF- coDF Anhydride; Compound 27a) [0149] A solution of 6.579 g DF and 7.35 ml TEA in 20.0 ml anhydrous chloroform was slowly added to a solution of 10.0 g compound 15d and 3.895 g compound 12b in 80 ml anhydrous chloroform at 0°C 4°C. The reaction mixture was stirred for 1 hour at O-L4'C, and washed with 100 ml 1N HC1, and 100 ml distilled water. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed in vacuo, and then the solid was dried in a vacuum oven at 40°C overnight. Fifteen g of the dried polymer were redissolved in 70 ml anhydrous chloroform and 0.625 ml TEA was added to the solution at 0°C. The reaction solution was stirred for 1 hour, and a solution of 87.2 mg triphosgene in 2.0 ml anhydrous chloroform at 0°C was slowly added. The reaction mixture was stirred for 1 hour at 0i4°C, and was washed with 100 ml 1N HC1 and 100 ml distilled water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed in vacuo at 40°C. The crude polymer was dissolved in 120 ml DCM, and then slowly added to 1. 2 1 anhydrous diethyl ether that was placed in a Teflon cylinder while stirring vigorously. The supernate was decanted, and the residue was washed with anhydrous ethyl ether. The thus obtained gummy polymer was transferred into a Teflon dish and dried in a vacuum oven at 40°C for 24 hours to obtain 11.4 g of product. MW=149, 000; PDI=2.36
  • 78
  • [ 846588-04-3 ]
  • [ 22494-42-4 ]
  • None [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane at 5℃; for 0.5h; 34 Example 34: Preparation of Random Poly (DF-C14-DF-coDF) Anhydride (Compound 27c) [0151] A mixture of 3.971 g DF and 4.64 ml TEA in 18 ml anhydrous DCM was added drop-wise to a solution of 10.0 g of DF-C14-DF diacid chloride (Compound 15d) in 30 rnl anhydrous DCM at 5 °C, and the reaction mixture was stirred for 30 minutes at 5°C. The mixture was then diluted with 40 ml DCM, washed with 100 ml IN HC1 and 100 ml distilled water, and dried over anhydrous magnesium sulfate. The solution was concentrated to about 50 ml in vacuo, and was poured into anhydrous diethyl ether in a Teflon cylinder with stirring to precipitate the product. The supernate was decanted, and the solid was washed with ethyl ether, and dried in a vacuum oven at 40°C overnight to obtain 9.3 g of the product. MW=106,000 ; PDI=1. 88
  • 79
  • [ 119-30-2 ]
  • [ 144025-04-7 ]
  • [ 22494-42-4 ]
YieldReaction ConditionsOperation in experiment
85% In an argon atmosphere,Ti (OEt) 4 (456 mg, 2 mmol) and 2 mL of THF were added to a 25 mL three-necked flask, and 17 mL of a 2,4-difluorophenylmagnesium bromide tetrahydrofuran solution was added dropwise at room temperature.(From 2,4-difluorobromobenzene according to literature methods [Osborne, C.A .; Endean, T.B.D .; Jarvo.E.R.Org.Lett., 2015, 17,5340.]; 1M in THF, 17mmol),After dripping, stirring was continued for 30 min, and the resulting mixture was set aside.Take another three-necked flask, add 5-iodosalicylic acid (1.32g, 5mmol) and 5mL THF under argon atmosphere, stir for a while,Add FeCl3 (81.2mg, 0.5mmol),TMEDA (232mg, 2.0mmol) and 8mL toluene (THF / toluene 3: 1),After stirring for about 10 minutes,Slowly add the prepared titanium reagent, and stir and reflux for 6 to 8 hours.The reaction was completed (TLC tracking). Dilute hydrochloric acid was added until the reaction was clear.The product was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, rotary evaporated, and separated by column chromatography to obtain 1.1 g of the product. Yield: 85%.
  • 80
  • [ 89-55-4 ]
  • [ 144025-04-7 ]
  • [ 22494-42-4 ]
YieldReaction ConditionsOperation in experiment
83% Stage #1: (2,4-difluorophenyl)magnesium bromide With titanium (IV) ethoxide In tetrahydrofuran for 0.5h; Inert atmosphere; Stage #2: 5-bromosalicyclic acid With iron(III) chloride; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran; toluene Inert atmosphere; Reflux; 2 Example 1. Preparation of diflunisal In an argon atmosphere,Ti (OEt) 4 (456 mg, 2 mmol) and 2 mL of THF were added to a 25 mL three-necked flask, and 17 mL of a 2,4-difluorophenylmagnesium bromide tetrahydrofuran solution was added dropwise at room temperature.(From 2,4-difluorobromobenzene according to literature methods [Osborne, C.A .; Endean, T.B.D .; Jarvo.E.R.Org.Lett., 2015, 17,5340.]; 1M in THF, 17mmol),After dripping, stirring was continued for 30 min, and the resulting mixture was set aside.Take another three-necked flask, add 5-iodosalicylic acid (1.32g, 5mmol) and 5mL THF under argon atmosphere, stir for a while,Add FeCl3 (81.2mg, 0.5mmol),TMEDA (232mg, 2.0mmol) and 8mL toluene (THF / toluene 3: 1),After stirring for about 10 minutes,Slowly add the prepared titanium reagent, and stir and reflux for 6 to 8 hours.The reaction was completed (TLC tracking). Dilute hydrochloric acid was added until the reaction was clear.The product was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, rotary evaporated, and separated by column chromatography to obtain 1.1 g of the product. Yield: 85%.
  • 81
  • [ 321-14-2 ]
  • [ 144025-04-7 ]
  • [ 22494-42-4 ]
YieldReaction ConditionsOperation in experiment
63% Stage #1: (2,4-difluorophenyl)magnesium bromide With titanium (IV) ethoxide In tetrahydrofuran for 0.5h; Inert atmosphere; Stage #2: 5-chloro-2-hydroxybenzoic acid With iron(III) chloride; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran; toluene Inert atmosphere; Reflux; 3 Example 1. Preparation of diflunisal In an argon atmosphere,Ti (OEt) 4 (456 mg, 2 mmol) and 2 mL of THF were added to a 25 mL three-necked flask, and 17 mL of a 2,4-difluorophenylmagnesium bromide tetrahydrofuran solution was added dropwise at room temperature.(From 2,4-difluorobromobenzene according to literature methods [Osborne, C.A .; Endean, T.B.D .; Jarvo.E.R.Org.Lett., 2015, 17,5340.]; 1M in THF, 17mmol),After dripping, stirring was continued for 30 min, and the resulting mixture was set aside.Take another three-necked flask, add 5-iodosalicylic acid (1.32g, 5mmol) and 5mL THF under argon atmosphere, stir for a while,Add FeCl3 (81.2mg, 0.5mmol),TMEDA (232mg, 2.0mmol) and 8mL toluene (THF / toluene 3: 1),After stirring for about 10 minutes,Slowly add the prepared titanium reagent, and stir and reflux for 6 to 8 hours.The reaction was completed (TLC tracking). Dilute hydrochloric acid was added until the reaction was clear.The product was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, rotary evaporated, and separated by column chromatography to obtain 1.1 g of the product. Yield: 85%.
  • 82
  • C7H3BrO3(2-)*2Na(1+) [ No CAS ]
  • [ 144025-04-7 ]
  • [ 22494-42-4 ]
YieldReaction ConditionsOperation in experiment
82% With titanium(IV) tetraethanolate; iron(III)-acetylacetonate; tributylphosphine In tetrahydrofuran at 25℃; Inert atmosphere;
  • 83
  • [ 98-96-4 ]
  • [ 22494-42-4 ]
  • C13H8F2O3*C5H5N3O [ No CAS ]
YieldReaction ConditionsOperation in experiment
In water at 20℃; Milling; 2.1. Chemicals and sample preparation Anhydrous solid-state DIF (purity 99%) was acquired by J&K ChemicalCompany (Shanghai, China). The sample PZA (purity 99%) was purchasedfromSigma-Aldrich Company (Shanghai, China). All compoundswere used as received without additional purification. The DIF-PZA drug-drug co-crystal was obtained by liquid assistedgrinding method, which is one of commonly used methods in the fieldof co-crystal preparation and analysis. At room temperature, the mixtureof molar ratio 1:1 stoichiometry of DIF (0.01 mol, ~250 mg) and PZA (0.01 mol, ~122 mg) was added in 25 ml stainless steel millingjars. Co-grinding the physical mixture was performed in an oscillatoryball mill (Mixer Mill MM400, with grinding-time lasting around60 min and frequency at 15 Hz), and several drops of water (around0.05 ml)was added to themixture compounds before starting mechanicalgrinding in the planetarymill. In order to design a set of control experiment,another physicalmixture was obtained by gently mixing twocompounds above with a 1:1 equal-molar ratio in a glass vial by using avortex mixer. Approximately 0.25 g DIF, PZA, physical mixture and thecorresponding co-crystal were weighed and they were ground gentlyto achieve particles with the mean size of several micrometers inorder to minimize the scattering effects from sample particles duringTHz spectralmeasurements. These samples were respectively preparedby using a hydraulic compression machine (HANDTAB-100, IchihashiSeiki, Kyoto, Japan) with a diameter of about 13.00mmand a thicknessof around 1.60 mm. The pressure is continuously applied for 30 s at aconstant pressure of around 4.0 MPa to obtain final pellets, and theyare sealed in plastic bags in order to avoid probable deliquescence atroom temperature before further THz spectral measurements. As forRaman spectral measurements, there is no need for further samplepreparation.
  • 84
  • [ 504-15-4 ]
  • [ 22494-42-4 ]
  • 7-(2,4-difluorophenyl)-1-hydroxy-3-methyl-9H-xanthen-9-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With methanesulfonic acid; phosphorus pentoxide at 90℃; 3.2. General procedure for preparation of substituted 1-hydroxy-3-methylxanthones General procedure: A mixture of phosphorus pentoxide (0.36 g, 2.5 mmol) and methanesulfonic acid(10 ml) was heated at 110 C until a clear solution was obtained. The temperature wasthen lowered to 90 C and a mixture of 3,5-dihydroxytoluene (0.13 g, 1.0 mmol) andsubstituted salicylic acid (1.0 mmol) was added. Heating was then continued for severalhours. The reaction progress was monitored by thin-layer chromatography (TLC)until the reaction was balanced, then the reaction mixture was poured into icedwater.The crude product was collected by filtration or extracted with ethyl acetate,washed with water, dried, and purified by medium pressure preparative chromatographywith ethyl acetate/petroleum ether to afford the target xanthone.
  • 85
  • [ 6066-82-6 ]
  • [ 22494-42-4 ]
  • 2,5-dioxopyrrolidin-1-yl 2',4'-difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
57% With dicyclohexyl-carbodiimide In tetrahydrofuran at 4 - 20℃; for 24h; 2 (2) Synthesis of GdL (6) as compound according to Example 1 of the present disclosure First, diflunisal (3 g, 12 mmol) was dissolved in 40 mL tetrahydrofuran (THF), and then N-hydroxysuccinimide (NHS) was added thereto, followed by stirring for 30 minutes. Then, N,N'-dicyclohexylcarbodiimide (DCC) dissolved in 30 mL THF was slowly added thereto at 4° C and then reaction thereof has occurred at room temperature for 24 hours. Then, an insoluble reactant was filtered therefrom, and the solvent was completely removed therefrom, and then, a resulting product was subjected to open column chromatography (DCM/MeOH, 99:1), thereby to separate and purify 2,5-dioxopyrrolidin-1-yl 2',4'-difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylate) (hereinafter, compound (3)) as a white colored solid (yield: 2.36 g (57%)).
57% Stage #1: 1-hydroxy-pyrrolidine-2,5-dione; 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid In tetrahydrofuran for 0.5h; Stage #2: With dicyclohexyl-carbodiimide In tetrahydrofuran at 4 - 20℃; for 24h; 1.2 (2) a compound according to an embodiment of the present invention: synthesis of MBP-11902 First, diflunisal (3 g, 12 mmol) was dissolved in 40 mL of tetrahydrofuran (THF) and N-hydroxysuccinimide (NHS) was added thereto, followed by stirring for 30 minutes. .Then, N,N'-dicyclohexylcarbodiimide (N,N'-Dicyclohexylcarbodiimide, DCC) dissolved in 30 mL THF was slowly added to the reaction product at 4 °C, and then reacted at room temperature for 24 hours. Then, after filtering the insoluble reactant and removing all the solvent, open column chromatography (DCM/MeOH, 99:1) as a solid having a white color,2,5-dioxopyrrolidin-1-yl 2',4'-difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylate (hereinafter, compound (3)) was separated and purified (yield: 2.36 g (57%)).
53.67% Stage #1: 1-hydroxy-pyrrolidine-2,5-dione; 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid In tetrahydrofuran at 20℃; for 0.5h; Stage #2: With dicyclohexyl-carbodiimide In tetrahydrofuran at 4℃;
  • 86
  • [ 22494-42-4 ]
  • [ 114937-32-5 ]
YieldReaction ConditionsOperation in experiment
95% With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; Reflux;
  • 87
  • [ 22494-42-4 ]
  • [ 121-87-9 ]
  • N-(2-chloro-4-nitrophenyl)-2’,4’-difluoro-4-hydroxy-[1,1‘-biphenyl]-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With phosphorus trichloride In 5,5-dimethyl-1,3-cyclohexadiene for 4h; Reflux; a) General procedure: The5-chloro-2-methoxybenzoic acid (0.1 g, 0.536 mmol) and 2-chloro-4-nitroaniline (0.092 g, 0.536 mmol) were suspended in dry Xylene (2.68 mL). After heating to reflux, Phosphorus trichloride (0.019 mL, 0.214 mmol) was added and the reaction mixture stirred under reflux for four hours. The reaction mixture was then cooled to RT and an equal volume of water was added. The mixtutre was stirred for 30 min and then pH was adjusted to >8 by adding sat. NaHCO3. The resultant mixture was then filtered and washed with Hexanes to get the dry solid. DMSO (5 mL) was added and the compound was dissolved via heating. On cooling, the pure compound crashed out. It was then filtered, washed with hexanes and dried to provide 5-chloro-N-(2-chloro-4-nitrophenyl)-2-methoxybenzamide (.125 g, 0.366 mmol, 68 % yield) as the pure product.
  • 88
  • [ 667-27-6 ]
  • [ 22494-42-4 ]
  • C17H12F4O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% With peracetic acid; <i>N</i>-<i>tert</i>-butoxycarbonyl-<i>L</i>-leucine; iron(II) diacetylacetonate In water; dimethyl sulfoxide at 80℃; for 6h; Green chemistry; 35 Synthesis of compound 35 In the air, add ferrous acetylacetonate (0.1mmol), N-BOC-L-leucine (0.2mmol), substrate 1ai (0.5mmol), dimethyl sulfoxide (1.5mL) and Water (0.5mL), BrCF2COOEt (1.5mmol)And peroxyacetic acid (1.5 mmol). After mixing uniformly at room temperature, the reaction mixture was reacted at 80°C for 6 hours.After the reaction is over, add 5 mL of water, and extract with ethyl acetate (petroleum ether: ethyl acetate V/V=10:3) (5 mL×3), combine the organic phases, wash with water (5 mL×3), collect the organic phase, and subtract After the solvent was removed by autoclaving, the product 35 was obtained by column chromatography and the yield was 52%.
  • 89
  • [ 66-71-7 ]
  • [ 22494-42-4 ]
  • uranyl(VI) acetate dihydrate [ No CAS ]
  • C38H26F4N2O8U [ No CAS ]
YieldReaction ConditionsOperation in experiment
38% With potassium hydroxide In methanol for 3h; 2.2.4. Synthesis of complexes 4-10 General procedure: Compounds 4-10 were prepared in a similar way. More specifically,a solution of each NSAID and KOH (except for complex 4) in methanol(0.4 mmol) was added to an aqueous solution of UO2(CH3COO)22H2O(0.2 mmol, 84 mg) in the presence or absence of a nitrogen-donor andwas stirred for 3 h. The procedure was completed by filtration, washingwith water and drying in vacuum of the precipitate collected.
  • 90
  • [ 17084-13-8 ]
  • [ 22494-42-4 ]
  • [GaIII(5-methyl-1,10-phenanthroline)2Cl2]Cl [ No CAS ]
  • [GaIII(5-methyl-1,10-phenanthroline)2(diflunisal)](PF6) [ No CAS ]
YieldReaction ConditionsOperation in experiment
91% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid; [GaIII(5-methyl-1,10-phenanthroline)2Cl2]Cl With caesium carbonate In methanol at 20 - 60℃; for 22h; Stage #2: potassium hexafluorophosphate In methanol; acetone
  • 91
  • [ 17084-13-8 ]
  • [ 22494-42-4 ]
  • [GaIII(3,4,7,8-tetramethyl-1,10-phenanthroline)2Cl2]Cl [ No CAS ]
  • [GaIII(3,4,7,8-tetramethyl-1,10-phenanthroline)2(diflunisal)](PF6) [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid; [GaIII(3,4,7,8-tetramethyl-1,10-phenanthroline)2Cl2]Cl With caesium carbonate In methanol at 20 - 60℃; for 22h; Stage #2: potassium hexafluorophosphate In methanol; acetone
  • 92
  • [ 17084-13-8 ]
  • [ 22494-42-4 ]
  • [GaIII(4,7-diphenyl-1,10-phenanthroline)2Cl2]Cl [ No CAS ]
  • [GaIII(4,7-diphenyl-1,10-phenanthroline)2(diflunisal)](PF6) [ No CAS ]
YieldReaction ConditionsOperation in experiment
87% Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid; [GaIII(4,7-diphenyl-1,10-phenanthroline)2Cl2]Cl With sodium carbonate In methanol at 20 - 60℃; for 96h; Stage #2: potassium hexafluorophosphate In methanol; acetone for 0.166667h;
  • 93
  • [ 10297-06-0 ]
  • [ 22494-42-4 ]
  • 2',4'-difluoro-4-(hex-5-yn-1-yloxy)-[1,1'-biphenyl]-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
87% With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 85℃; for 24h;
Same Skeleton Products
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