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Chemical Structure| 25392-41-0
Chemical Structure| 25392-41-0
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Product Details of [ 25392-41-0 ]

CAS No. :25392-41-0 MDL No. :MFCD00467168
Formula : C10H7ClO3 Boiling Point : -
Linear Structure Formula :- InChI Key :TXSLBPGPBNGHRW-UHFFFAOYSA-N
M.W : 210.61 Pubchem ID :5398846
Synonyms :

Calculated chemistry of [ 25392-41-0 ]

Physicochemical Properties

Num. heavy atoms : 14
Num. arom. heavy atoms : 10
Fraction Csp3 : 0.1
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 54.27
TPSA : 50.44 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.22 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.61
Log Po/w (XLOGP3) : 1.92
Log Po/w (WLOGP) : 2.09
Log Po/w (MLOGP) : 1.63
Log Po/w (SILICOS-IT) : 2.91
Consensus Log Po/w : 2.03

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.82
Solubility : 0.32 mg/ml ; 0.00152 mol/l
Class : Soluble
Log S (Ali) : -2.6
Solubility : 0.526 mg/ml ; 0.0025 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.06
Solubility : 0.0182 mg/ml ; 0.0000863 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.52

Safety of [ 25392-41-0 ]

Signal Word:Danger Class:8
Precautionary Statements:P260-P264-P270-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P405-P501 UN#:3261
Hazard Statements:H302-H314 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 25392-41-0 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 25392-41-0 ]
  • Downstream synthetic route of [ 25392-41-0 ]

[ 25392-41-0 ] Synthesis Path-Upstream   1~5

  • 1
  • [ 25392-41-0 ]
  • [ 69716-04-7 ]
YieldReaction ConditionsOperation in experiment
93.75%
Stage #1: for 2 h; Reflux
Stage #2: With sulfuric acid In water at 20℃;
Intermediate 89: (6-Hydroxy-1-benzofuran-3-yl) acetic acidA mixture of the obtained 4-(chloromethyl)-7-hydroxy-2/- -chromen-2-one (21.0 g, 21.0 mmol) and 1 M aqueous sodium hydroxide solution (1 L) was stirred at reflux for 2 h. The reaction mixture was acidified with concentrated sulfuric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulphate and concentrated to give (6-Hydroxy-1-benzofuran-3-yl) acetic acid (18.0 g, 93.75 percent).
83%
Stage #1: for 2 h; Heating / reflux
Stage #2: With sulfuric acid In water
Reference Example 29; (6-hydroxy-l-benzofuran-3-yl) acetic acid; 4- (Chloromethyl)-7-hydroxy-2H-chromen-2-one (10.9 g, 51.8 mmol) was dissolved in 1 M aqueous sodium hydroxide solution (500 mL) , and the mixture was heated under reflux for 2 hr.The reaction mixture was allowed to cool, acidified with concentrated sulfuric acid, and extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (8.27 g, yield 83percent) as brown crystals .MS m/z 193 (M + H)+.
52%
Stage #1: With sodium hydroxide In water at 20 - 60℃; for 5 h; Cooling with ice
Stage #2: With hydrogenchloride In water at 20 - 35℃; for 2 h;
Sodium hydroxide (1.35 g, 34 mmol) was dissolved in water (8 mL), under ice bath was slowly added 4-(chloromethyl) -7-hydroxy-2H-benzopyran-2-one (2.5 g, 12 mmol) in water (6 mL). The mixture was stirred at room temperature for 1 hour and then reacted at 60 ° C for 4 hours. Concentrated hydrochloric acid (2.8 mL, 34 mmol) was added at 35 ° C, maintained at the temperature for 1 hour, then stirred at room temperature for 1 hour. The resulting solid was suction filtered and washed three times with water. The solid was dried to give the product as a white solid (1.2 g, 52percent yield).
1.3 g for 2 h; Reflux 4-chloroacetoacetate (4.25 ml, 31.43 mmol) was dissolved in 20 ml of concentrated sulfuric acid at 0 ° C, The resulting pale yellow viscous solution was placed in an ice bath and cooled to about _5 ° C, Resorcinol (3.15 g, 28.57 mmol) was added in portions, Control the internal temperature below 0 ° C, plus complete, room temperature stirring 2 h, The reaction solution was poured into 50 ml of ice water and precipitated as a white solid. The filtrate was filtered, washed with water (5 ml x2) and dried to obtain 5.6 g of a white solid and 82percent of the crude product. [0085] Take the crude product (2 g, 9.50 mmol) in 200 ml single-necked flask and add IN NaOH solution (100 ml). The solution immediately became concentrated yellow. The solution was heated in an oil bath for 2 h. Finished, cooled to room temperature, with concentrated sulfuric acid regulation PH to 2-3, the resulting solution was extracted with ethyl acetate (30 ml X4). The organic phases were combined, washed with saturated brine (20 ml X2), dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated under reduced pressure. Brown columnar crystals 1.3 g, crude yield 71.2percent.(1 g, 5.20 mmol) was suspended in 10 ml of methanol, 0.5 ml of concentrated sulfuric acid was added dropwise, and the reaction was refluxed for about 4 hours. After completion of the reaction, the methanol was distilled off under reduced pressure and the residual liquid was poured into 30 ml The mixture was extracted with ethyl acetate (20 ml x3) and the organic phases were combined, washed with saturated sodium bicarbonate solution (15 ml X), washed with saturated brine (15 ml X), dried over anhydrous sodium sulfate, filtered, The filtrate was evaporated under reduced pressure to give a yellowish brown oil which was purified by column chromatography (petroleum ether / ethyl acetate, 80: 20, v / v) to give 0.75 g of a pale yellow solid in 70percent yield.

Reference: [1] Heterocycles, 1995, vol. 41, # 4, p. 647 - 650
[2] Patent: WO2012/11125, 2012, A1, . Location in patent: Page/Page column 136-137
[3] Patent: WO2008/1931, 2008, A2, . Location in patent: Page/Page column 87
[4] Journal of Medicinal Chemistry, 2012, vol. 55, # 4, p. 1538 - 1552
[5] Patent: CN104250239, 2016, B, . Location in patent: Paragraph 0292; 0293; 0294
[6] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 13, p. 3630 - 3635
[7] ChemMedChem, 2010, vol. 5, # 9, p. 1577 - 1593
[8] Patent: WO2012/111849, 2012, A1, . Location in patent: Page/Page column 142-143
[9] Patent: CN105566267, 2016, A, . Location in patent: Paragraph 0092; 0094; 0096
[10] Patent: CN105566263, 2016, A, . Location in patent: Paragraph 0081-0085
[11] Patent: CN105017242, 2018, B, . Location in patent: Paragraph 0077; 0079; 0081
  • 2
  • [ 638-07-3 ]
  • [ 108-46-3 ]
  • [ 25392-41-0 ]
YieldReaction ConditionsOperation in experiment
91% at 90℃; for 5 h; General procedure: A mixture of phenol (1.0 mmol), β-ketoester (1.5 mmol) and MNESA (0.075 g) was stirred at 90 °C in a round-bottomed flask for the appreciated time. After completion of the reaction as confirmed by TLC, the reaction mixture was cooled down to room temperature and the catalyst was separated from the reaction mixture using an external magnetic Some field. water was then added to the reaction mixture and the product was extracted using EtOAc (2 9 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuumto yield the crude product. For more purification, the crude product was purified by recrystallization in ethanol to obtain the desired purity.
91% With Ag supported on the hydroxyapatite-core–shell magnetic γ-Fe2O3 nanoparticles In neat (no solvent) at 80℃; for 0.333333 h; Green chemistry General procedure: In a round bottom flask, g-Fe2O3HAp-Ag NPs (10 mg) were added to the mixture of the phenolic compound (1 mmol) and ethyl acetoacetate (1 mmol) at 80 C and the reaction mixture stirred for the appropriate time (Table 3). The progress of the reaction was monitored by TLC (eluent, n-hexane:ethyl acetate, 4:1) analysis. Upon completion of the reaction, EtOH was added to the reaction mixture and the g-Fe2O3HAp-Ag NPs were separated with an external magnet. The solvent was then removed under reduced pressure and the resulting product was purified by recrystallization using ethanol. The coumarin derivatives were obtained in good to excellent isolated yields (83percent–96percent).
84% at 20℃; for 2 h; Reference Example 28; 4- (chloromethyl) -7-hydroxy-2H-chromen-2- one; <n="88"/>Under ice-cooling, ethyl 4-chloroacetoacetate (14.0 g, 85.0 mmol) was dissolved in concentrated sulfuric acid (30 mL) , resorcinol (8.81 g, 80.0 mmol) was added by small portions, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into ice water, and the precipitated solid was collected by filtration, washed with water, and air-dried to give the title compound (14.1 g, yield 84percent) as a beige powder. MS m/z 211 (M + H)+.
84% at 20℃; Cooling with ice Example 30: 7-(3-(4-(3-(6-fluoro-benzisoxazole)-1-piperidyl)-n-propoxy))-4-hydroxymethyl-2H-benzopyran-2-one (30) [0067] The target compound was synthesized according to Scheme 3. 1) 50 ml of concentrated sulfuric acid was stirred in an ice bath, to which was added 5.5 g of resorcinol and added 8 g of 4-chloro ethyl acetoacetate dropwsie. The solution turned yellowish and turbid slowly. The reaction was performed at room temperature overnight. The reaction liquid was poured into ice/water mixture, and a lot of white solid was precipitated, which was filtrated. The cake was washed with water. The cake was recrystallized with 40percent ethanol to give 7.5 g of white crystal. Melting point: 183-185°C, yield: 84percent.
84% at 20℃; 1) 50 ml of concentrated sulfuric acid was stirred in an ice bath, to which was added 5.5 g of resorcinol and added 8 g of 4-chloro ethyl acetoacetate dropwise. The solution turned yellowish and turbid slowly. The reaction was performed at room temperature overnight. The reaction liquid was poured into ice/water mixture, and a lot of white solid was precipitated, which was filtrated. The cake was washed with water. The cake was recrystallized with 40percent ethanol to give 7.5 g of white crystal. Melting point: 183-185° C., yield: 84percent.
84% With nanosilica molybdic acid 2 In neat (no solvent) at 80℃; for 0.333333 h; Green chemistry General procedure: In a general experimental procedure, β-ketoester 3(1 mmol) was added to a mixture of substituted phenol4 (1 mmol) and SMA NPs 2 (5 molpercent) in a solvent-freetube. The reaction mixture was stirred in a preheated oilbath (80 °C). After the completion of the reaction, the precipitateobtained was extracted with ethyl acetate, washedwith water (3 × 10 ml) and dried to obtain the product.The remaining insoluble solid catalyst in aqueous phasewas separated by filtration, washed with ethyl acetate
75.6% at 0 - 20℃; for 2 h; Intermediate 88: 4-(Chloromethyl)-7-hydroxy-2tf-chromen-2-oneTo a 250 mL RB flask fitted with magnetic stirrer was charged with Ethyl 4- chloroacetoacetate (22.12 g, 134.9 mmol) was dissolved in concentrated sulfuric acid (48 mL) at 0 , and resorcinol (14.0 g, 127.3 mmol) was ad ded portionwise. The mixture was stirred at room temperature for 2 h. The reaction mixture was poured into ice-water, and the resulting solid was collected by filtration, washed with water, and dried to give 4- (chloromethyl)-7-hydroxy-2H-chromen-2-one (21.0 g, 75.6 percent) as a beige solid.
70% at 65℃; for 5 h; A resorcinol (5.5 g, 0.05 mol)Ethyl 4-chloroacetoacetate (9.9 g, 0.06 mol)Anhydrous bismuth chloride (0.8 g, 2.5 mmol)Mixed in a 100 mL round bottom flask,It was heated in the absence of a solvent The reaction was stirred 65 , 5h,After the reaction,Add 16 mL of 50percent aqueous ethanol solution,Continue to stir at 65 ° C for 10 min,Cooled to room temperature, suction filtration, solid parts washed to neutral,Dried to give 7.45 g of a white solid,Is 4-chloromethyl-7-hydroxycoumarin, the yield of 70percent.
67% With sulfuric acid In acetic acid at 60℃; for 4 h; Cooling with ice M-bisphenol (27.5 g, 250 mmol) was placed in acetic acid (60mL) heated to 50 ° C for use, ethyl 4-chloroacetoacetate(20.5 g, 125 mmol) was dissolved in acetic acid (20 mL), cooled in an ice-water bath, concentrated sulfuric acid (10 mL) was slowly added, then, the acetic acid solution of m-bisphenol was added to the ice-water bath, stirred at room temperature for 1 hour, and then reacted at 60 deg. C for 3 hours. After completion of the reaction, water (300 mL) was added and the mixture was stirred at room temperature for 1 hour. The resulting white solid was suction-washed three times with water (100 mL) and dried to give the product (17.6g, 67percent yield).
60% With methanesulfonic acid In toluene at 80 - 110℃; Resorcinol (2 g, 18.18 mmol) was dissolved in 50 mL of hottoluene (80 oC). Chloroacetoacetate (3.5 g, 18.18 mmol, 3 mL)was added and allowed to dissolve. The solution was heated to110 oC and methanesulfonic acid (1 mL) was added. After 1 h,the hot toluene containing the product was decanted. The product crystallized uponcooling, it was filtered and dried under vacuum. The resulting gum from thedecanting step was re-suspended in toluene, heated and decanted. The procedurewas repeated until most of product 5 was recovered as a light brown solid (2.3 g,60percent yield).
45.7% at 0℃; for 2 h; 4-Chloromethyl-7-hydroxy-2H-chromen-2-oneResorcinol (7.0 g, 63.6 mmol), ethyl 4-chloroacetoacetate (9.5 ml, 69.9 mmol) and 104 ml of 96percent sulphuric acid were stirred for 2 hours at 0 0C. The reaction mixture was poured into ice water (200 ml) and extracted with ethyl acetate. The organic layers were collected, washed with NaHCO3 10percent aqueous solution, then with water, dried over sodium sulphate and evaporated under vacuum. The resulting oil was purified by column chromatography on silica gel (eluant CHCl3/AcOEt 7.5/2.5 v/v) yielding 5.22 g (45.7percent) of a white solid used without any further purification for the next step synthesis.1H-NMR (Acetone-d6) δ: 9.50 (s, IH, exchanges with D2O), 7.73 (d, IH5 J=8.8), 6.91(dd, IH, J=8.8, J=2.5), 6.80 (d, IH, J=2.5), 6.40 (s, IH), 4.92 (s, 2H).
23.4 g at 40 - 50℃; for 2 h; Step 1: 4-Chloromethyl-7-hydroxy-chromen-2-one [0239] 33.5 g (304 mmol) resorcine is dissolved in 105 ml acetic acid at 40° C. 25.0 g (152 mmol) 4-chloroacetic acid ethylester is added and the funnel is rinsed with 10 ml acetic acid. Then, 26.8 g (274 mmol) conc. H2SO4 (97percent) is added and the funnel is rinsed with 10 ml acetic acid. The mixture is heated to 50° C. for approx. 2 h. After full conversion, 330 ml water is added. The reaction mixture is cooled to r.t. and the suspension is stirred overnight. The product is filtered off, washed with water (2×50 ml) and dried. Yield: 23.4 g; Rf=0.42 (silica gel, PE/EtOAc=6/4); Mass spectrum (ESI): m/z=211 [M+H]+.
23.4 g With sulfuric acid In acetic acid at 40 - 50℃; for 0.2 h; Step 1:
4-chloromethyl-7-hydroxy-chromen-2-one
33.5 g (304 mmol) resorcine is dissolved in 105 ml acetic acid at 40 °C. 25.0 g (152 mmol) 4-chloroacetic acid ethylester is added and the funnel is rinsed with 10 ml acetic acid. Then, 26.8 g (274 mmol) cone. H2S04(97percent) is added and the funnel is rinsed with 10 ml acetic acid. The mixture is heated to 50 °C for approx. 2 h. After full conversion, 330 ml water is added. The reaction mixture is cooled to r.t. and the suspension is stirred overnight. The product is filtered off, washed with water (2 x 50 ml) and dried. Yield: 23.4 g; Rf= 0.42 (silica gel, PE/EtOAc = 6/4); Mass spectrum (ESI): m/z = 21 1 [M + H]+
5.6 g at 0℃; for 2 h; 4-chloroacetoacetate (4.25 ml, 31.43 mmol) was dissolved in 20 ml of concentrated sulfuric acid at 0 ° C, The resulting pale yellow viscous solution was placed in an ice bath and cooled to about _5 ° C, Resorcinol (3.15 g, 28.57 mmol) was added in portions, Control the internal temperature below 0 ° C, plus complete, room temperature stirring 2 h, The reaction solution was poured into 50 ml of ice water and precipitated as a white solid. The filtrate was filtered, washed with water (5 ml x2) and dried to obtain 5.6 g of a white solid and 82percent of the crude product. [0085] Take the crude product (2 g, 9.50 mmol) in 200 ml single-necked flask and add IN NaOH solution (100 ml). The solution immediately became concentrated yellow. The solution was heated in an oil bath for 2 h. Finished, cooled to room temperature, with concentrated sulfuric acid regulation PH to 2-3, the resulting solution was extracted with ethyl acetate (30 ml X4). The organic phases were combined, washed with saturated brine (20 ml X2), dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated under reduced pressure. Brown columnar crystals 1.3 g, crude yield 71.2percent.(1 g, 5.20 mmol) was suspended in 10 ml of methanol, 0.5 ml of concentrated sulfuric acid was added dropwise, and the reaction was refluxed for about 4 hours. After completion of the reaction, the methanol was distilled off under reduced pressure and the residual liquid was poured into 30 ml The mixture was extracted with ethyl acetate (20 ml x3) and the organic phases were combined, washed with saturated sodium bicarbonate solution (15 ml X), washed with saturated brine (15 ml X), dried over anhydrous sodium sulfate, filtered, The filtrate was evaporated under reduced pressure to give a yellowish brown oil which was purified by column chromatography (petroleum ether / ethyl acetate, 80: 20, v / v) to give 0.75 g of a pale yellow solid in 70percent yield.
0.188 g at 0℃; Cooling with ice Under the condition of the ice, will be 1.10 g resorcinol is dissolved in concentrated sulfuric acid in the amount of drying, stirring to completely dissolve, slowly dropping 1.62 ml of 4 - chloro acetyl ethyl acetate, its temperature is 0 °C, after dropping, is moved to the reaction at room temperature, stirring overnight, the reaction [...] poured into ice water, stirring, to be solid after fully depositing, filtering and drying, to obtain 0.188 g intermediate 1, name for 4 - chloro methyl -7 - hydroxy coumarin

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  • 3
  • [ 32807-28-6 ]
  • [ 108-46-3 ]
  • [ 25392-41-0 ]
YieldReaction ConditionsOperation in experiment
65% With toluene-4-sulfonic acid In toluene at 110℃; for 0.75 h; Dean-Stark 1 : To a stirring solution of resorcinol (10 g, 91 mmol, 1 equiv) and 4-chloromethyl acetoacetate (17 g, 103 mmol, 1.14 equiv) in toluene (150 mL) was added p-toluenesulfonic acid (3.6 g, 19 mmol, 0.21 equiv). The solution was connected to a Dean-Stark apparatus and heated to reflux at 1 10 °C for 45 min. The reaction mixture was concentrated and purified by column chromatography (EtOAC:CH2Cl2 1 :9) to yielded a white solid 1 (12 g, 65percent yield).
65% With toluene-4-sulfonic acid In toluene at 110℃; for 0.75 h; Resorcinol (10 g, 91 mmol) was reacted with 4-chloromethyl acetoacetate (17 g, 103 mmol) in the presence of p-toluenesulfonic acid (3.6 g, 19 mmol) in toluene (150 mL) and refluxed at 110 °C for 45 minutes. The reaction mixture was purified by extraction in water and ethyl acetate and dried under vacuum. Further purification was done via silica gel liquid column chromatography (ethyl acetate: hexanel:9) to yield 7-hydroxy-4-(chloromethyl)coumarin (1) (12 g, 65percent yield). Then, compound (1) (2.95 g, 14 mmol) was refluxed over a stirring solution of water (350 mL) for 3 days to hydrolyze the chloromethyl into a hydroxymethyl group. The reaction mixture was filtered while hot, and cooled to room temperature over 12 h to yield 7-hydroxy-4-(hydroxymethyl)coumarin (2) (2.7 g). The product was used further without purification. The final 7-(hydroxypropoxy)-4-(hydroxymethyl)coumarin (3) was synthesized by combining (2) (1.0 g, 5.2 mmol) with potassium carbonate (2 g, 14.5 mmol), 18-crown-6 (0.7 g, 2.65 mmol), and 3-bromo-1-propanol (1.5 g, 10.8 mmol) and dissolving in dry acetone (15 mL) and refluxing at 55 °C for 2.45 hours in a CEM Discover microwave reactor. The reaction mixture was filtered and solvent was removed under reduced pressure and purified via silica gel liquid column chromatography using a mixture of ethyl acetate and hexane as the mobile phase. The product was dried under reduced pressure to yield pure (3) (1.18 g, 91percent). The coumarin monomers were characterized by 1HNMR.
Reference: [1] Heterocycles, 2007, vol. 71, # 12, p. 2721 - 2733
[2] Patent: WO2014/74845, 2014, A1, . Location in patent: Paragraph 0087
[3] Patent: US2017/172147, 2017, A1, . Location in patent: Paragraph 0080
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Reference: [1] Comptes Rendus Chimie, 2013, vol. 16, # 3, p. 271 - 278
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  • [ 805250-17-3 ]
Reference: [1] Patent: WO2012/11125, 2012, A1,
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 4, p. 1538 - 1552
[3] Patent: CN105566267, 2016, A,
[4] Patent: CN104250239, 2016, B,
[5] Patent: CN105566263, 2016, A,
[6] Patent: CN105017242, 2018, B,
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