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[ CAS No. 21739-92-4 ] {[proInfo.proName]}

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Chemical Structure| 21739-92-4
Chemical Structure| 21739-92-4
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Product Details of [ 21739-92-4 ]

CAS No. :21739-92-4 MDL No. :MFCD00002415
Formula : C7H4BrClO2 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 235.46 Pubchem ID :-
Synonyms :

Calculated chemistry of [ 21739-92-4 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 46.11
TPSA : 37.3 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) : -5.69 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.64
Log Po/w (XLOGP3) : 2.88
Log Po/w (WLOGP) : 2.8
Log Po/w (MLOGP) : 2.94
Log Po/w (SILICOS-IT) : 2.54
Consensus Log Po/w : 2.56

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.45
Solubility : 0.0832 mg/ml ; 0.000353 mol/l
Class : Soluble
Log S (Ali) : -3.32
Solubility : 0.112 mg/ml ; 0.000475 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.25
Solubility : 0.134 mg/ml ; 0.000568 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.5

Safety of [ 21739-92-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 21739-92-4 ]

* 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.

  • Upstream synthesis route of [ 21739-92-4 ]
  • Downstream synthetic route of [ 21739-92-4 ]

[ 21739-92-4 ] Synthesis Path-Upstream   1~26

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Reference: [1] Tetrahedron Letters, 1997, vol. 38, # 9, p. 1559 - 1562
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YieldReaction ConditionsOperation in experiment
100% With oxalyl dichloride In DMF (N,N-dimethyl-formamide); dichloromethane at 20 - 25℃; 8.00 kg 2-chloro-5-bromobenzoic acid was suspended in 80.00 L methylene chloride (KF of methylene chloride <0.1percent H2O) and 0.02 L of DMF added at 20 C. 5.18 Kg oxalyl chloride were slowly added and the internal temperature maintained below 25 C. The addition was slightly exothermic; gas evolution of HCl and CO2 occurred. The reaction was run at 20-25 C. overnight; a clear solution was obtained. The mixture was concentrated in vacuum to an oily residue and degased at 40 C. in vacuum. Yield of 2-chloro-5-bromobenzoic acid chloride: 8.63 kg (33.98 mol, yield 100.0percent)
100% With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at -5 - 30℃; for 5 h; Inert atmosphere 5-bromo-2-chlorobenzoic acid 9a (120 g, 0.51 mol) was dissolved in dichloromethane (500 mL) and cooled under nitrogenTo a solution of oxalyl chloride (86 mL, 1000 mmol) and N, N-dimethylformamide (2.5 mL, 32 mmol) was added dropwise to -5 ° C,The reaction was stirred at room temperature for 5 hours. Concentration under reduced pressure gave the title compound 9b as a yellow oil (131 g, 100percent).
100% With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 10 - 40℃; Inert atmosphere 5g of 2-chloro-5-bromobenzoic acid and 30mL of dichloromethane were added into a 100mL reaction flask under nitrogen atmosphere, and then 0.16g of N, N-dimethylformamide was added, and at the temperature of 10-15 ° C, 3.2g Oxalyl chloride, incubated at the end of the reaction dropwise 1h, and then warmed to 35-40 ° C for 2-3hrs, after the end of the reaction vacuum distillation, steamed to solvent-free fractions, and then added 30mL dichloromethane vacuum distillation, to be dried residual oxalyl chloride , Pale yellow viscous material 6.9g, namely 2-chloro-5-bromobenzoyl chloride, yield 100percent.
100% With oxalyl dichloride In dichloromethane at -5℃; for 4 h; Inert atmosphere 5-Bromo-2-chlorobenzoic acid 11a (93.0 g, 395 mmol) was dissolved in dichloromethane (900 mL).Cool to -5 ° C under nitrogen, add oxalyl chloride (50 mL, 590 mmol)And N,N-dimethylformamide (1.0 mL, 12.9 mmol), and the mixture was stirred and stirred at room temperature for 4 hr.After the reaction was completed, it was concentrated under reduced pressure.The title compound 11b (107 g, yellow oil) was obtained.Yield: 100percent.
100% With thionyl chloride In dichloromethane at 40℃; for 3 h; To a 250 mL single-mouth bottle was added 2-chloro-5-bromobenzoic acid (Compound 2) (9.40 g, 40 mmol, 1.0 eq) and dichloromethane (70 mL).Then, thionyl chloride (8.70 mL, 120 mmol, 3.0 eq) was added and the reaction was stirred at 40 ° C for 3 hours.After completion of the reaction, it was concentrated to dryness to give 10.20 g of Compound A, yield 100percent, and used directly for the next reaction.
98.13% With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; Cooling with ice 2-chloro-5-bromobenzoic acid 0.59g (2.51mmol) in 15mL three-necked flask, 5ml of anhydrous dichloromethane, and the reaction flask is placed in ice-water, stirred for ten minutes. Then, a solution of 0.31ml (3.00mmol) of oxalyl chloride, reacted at room temperature overnight. After completion of the reaction, the solvent was evaporated to give 0.62g (2.46mmol) of a yellow solution (2), a yield of 98.13percent.
97% With pyridine; thionyl chloride In dichloromethane at 20℃; for 3.5 h; Reflux Step 1. Dissolve 5-bromo-2-chlorobenzoic acid (100 g, 0.43 mol) in 500 ml of methylene chloride, catalyze the addition of 1 g of pyridine, add thionyl chloride (60.5 g, 0.51 mol) dropwise at room temperature, and heat up to 40 °C reflux 3.5 hours,The reaction was completed by TLC, and dichloromethane was concentrated under reduced pressure to obtain 104 g of 5-bromo-2-chlorobenzoyl chloride (yield: 97percent), which was used as the next step without further purification.
94% With thionyl chloride In N,N-dimethyl-formamide; toluene at 0 - 100℃; for 5 h; Step 2
2-chloro-5-bromo-benzoyl chloride
Under Ar protection, 5-bromo-2-chloro-benzoic acid (35 g, 148.6 mmol) was dissolved in toluene (230 ml), followed by addition of DMF (0.5 mL) at room temperature, then the reaction mixture was cooled to 0° C.
The reaction mixture was heated to 100° C. after thionyl chloride (44 g, 372 mmol) was dropwise added.
After 5 hours, the reaction mixture was concentrated under reduced pressure to obtain the title compound 5-bromo-2-chloro-benzoyl chloride 12n (35.5 g, pale yellow grease), yield: 94.0percent.
94.7% With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 3 h; 5-Bromo-2-chlorobenzoic acid (14.128 g, 60 mmol) was added DCM (70 mL), DMF (0.132 g, 0.03 eq), Stir, Slowly add oxalyl chloride (5.6 ^, 1.1 called), After the drop was completed at room temperature reaction 31 , Concentrated under reduced pressure to give a pale yellow oil, DCM (70 mL) was added, Adding fluorobenzene (5.7668,169), Ice bath under the addition of 41 (: 13 (88,169), After adding 5 hours at room temperature, After TLC detection reaction was completed, Ice bath slowly add water (70mL), After stirring, The organic phase was washed with 10percent NaCl (50 mL) The organic phase was concentrated under reduced pressure to give a pale yellow oil, Isopropyl alcohol (70 mL) was added, Add water (70mL), Ice bath stirring crystallization 2h, Filter, The filter cake was washed with isopropanol / water (1: 1) mixed solution (20 mL) Dried to give the compound A as a pale yellow solid, 17.817g, yield: 94.7percent, purity: 99.12percent.

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Reference: [1] Patent: US2006/251728, 2006, A1, . Location in patent: Page/Page column 5-6
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YieldReaction ConditionsOperation in experiment
87.8% With sodium periodate; sulfuric acid; sodium bromide In water; acetic acid at 30 - 65℃; First, sodium periodate solution was configured: 5.5 g (25.56 mmol) of sodium periodate was dissolved in 38 ml of water and 23 ml of acetic acid.Next, add 10 g (63.9 mmol) of 2-chlorobenzoic acid, 6.6 g (63.9 mmol) of sodium bromide and sodium periodate solution to the reaction flask and heat to 30°C.At this temperature, 5.6 ml of concentrated sulfuric acid was slowly added dropwise. After completion of the dropwise addition of concentrated sulfuric acid, the temperature was raised to 50-65°C and reacted at this temperature for 2-3 hours.Thin layer chromatography (TLC) detection reaction is completed, cooled, poured into ice water, solid precipitated, filtered,The filter cake was washed with water several times to obtain the product 2-chloro-5-bromobenzoic acid 13.2 g, yield 87.8percent.
Reference: [1] Patent: CN107954852, 2018, A, . Location in patent: Paragraph 0032-0034
[2] Journal of the Indian Chemical Society, 1980, vol. 57, # 6, p. 640 - 642
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YieldReaction ConditionsOperation in experiment
92.1% With tetrachloromethane; molybdenum hexacarbonyl In dimethyl sulfoxide at 150℃; for 6 h; Autoclave This example is the preparation of 2-chloro-5-bromo-benzoic acid, and the specific method is as follows:2.14 g of molybdenum hexacarbonyl (0.01 mol) was added to a 1 L autoclave.217.0 g of 2-hydroxy-5-bromobenzoic acid (1.0 mol),185.0 g of carbon tetrachloride (1.2 mol) and 250 mL of dimethyl sulfoxide,Heat to 150 ° C,The reaction was stirred for 6 h.After the end of the controlled reaction in HPLC,Evaporate the solvent under reduced pressure.Then add 250 mL of acetonitrile,Warm up to 70 ° C and stir to dissolve.Then add neutral alumina for hot filtration.The filtrate was cooled to room temperature.A pale yellow solid precipitated.Then, 564 mL of an ethanol/water mixed solvent (volume ratio 1:3) was added.After heating and dissolving,Slowly cool to 60 ° C first,After a small amount of crystals are precipitated,Cooled to 50 ° C for 1 h,Finally, it was slowly cooled to 28 ° C and stirred for 3 h.filter,Collecting white solids,Washed twice in cold water and dried.217.0 g of white solid 2-chloro-5-bromo-benzoic acid were obtained.The yield was 92.1percent and the purity was 99.9percent (HPLC).
Reference: [1] Patent: CN108250060, 2018, A, . Location in patent: Paragraph 0016; 0059-0062
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YieldReaction ConditionsOperation in experiment
90%
Stage #1: for 6 h;
Stage #2: at 100℃; for 5 h;
into a 250ml reaction flask added the 46g O-chlorobenzotrichloride (0.2mol, 1eq) and 0.2g Fe powder. Stirring at room temperature, and added the drops of 35g Br2, after that maintain the reaction temperature at 35-40 ° C for 6 h. Ventilation with nitrogen will blow out excess Br2, and absorbed with alkali. Cooled at 10 ° C, and added the drops of 60 g of concentrated sulfuric acid (exothermic, dripping speed control to prevent the flow), after that heated at 100 ° C for 5 h; temperature get down at 60 ° C below, then slowly added the drops of 150mL water(intense heat, gas overflow, strictly control the drop speed to prevent the flow), and maintain 60-80 ° C stirring for 1h, than after gradually cooling to 15 ° C, the mixture has been filtered and washed with 100 mL of water, after that obtained the white crude, the purity of the crude product is 91percent and yield is 99percent. The crude product has been recrystallized with 60percent aqueous acetic acid, then obtained white solid 42.0g (yield 90percent, HPLC purity is 98.8percent).
Reference: [1] Patent: CN105622382, 2016, A, . Location in patent: Paragraph 0053; 0054
[2] Patent: CN107162894, 2017, A, . Location in patent: Paragraph 0033; 0034; 0035; 0036; 0037; 0038; 0039-0047
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YieldReaction ConditionsOperation in experiment
89.1% at 0 - 20℃; for 12 h; 60.00 g (0.26 mol) of 5_bromo-2-chlorobenzoic acid (1) was added to 200 mL of dry dichloromethane. 1.5 mL (5.2 mol) of DMF was added dropwise, and 32 mL (0.39 mmol) of oxalyl chloride was slowly dropped into the reaction solution four times under ice-cold bath conditions, and the temperature of the reaction solution was required to be between 0 and 5 ° C. The solution was slowly warmed to room temperature for 12 h. The reaction was monitored by thin layer chromatography TLC until the reaction of the starting material was completed, and solvent and oxalyl chloride were evaporated under reduced pressure. The oxalyl chloride was distilled off three times with dichloromethane, and cooled to give a white solid (2) 53.5 g. Yield 89.1percent
Reference: [1] Patent: CN108285439, 2018, A, . Location in patent: Paragraph 0038; 0091-0093
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Reference: [1] Angewandte Chemie - International Edition, 2017, vol. 56, # 14, p. 3867 - 3871[2] Angew. Chem., 2017, vol. 129, # 14, p. 3925 - 3929,5
[3] ChemCatChem, 2018, vol. 10, # 6, p. 1253 - 1257
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Reference: [1] Tetrahedron Letters, 1997, vol. 38, # 9, p. 1559 - 1562
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  • [ 106-39-8 ]
  • [ 124-38-9 ]
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Reference: [1] Tetrahedron Letters, 1997, vol. 38, # 9, p. 1559 - 1562
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Reference: [1] Journal of Organic Chemistry, 1957, vol. 22, p. 1096
[2] Journal of the Chemical Society, 1904, vol. 85, p. 1269
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Reference: [1] Journal of the Chemical Society, 1953, p. 232,236
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Reference: [1] Journal of the Chemical Society, 1904, vol. 85, p. 1269
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YieldReaction ConditionsOperation in experiment
45% With potassium <i>tert</i>-butylate In tetrahydrofuran; water EXAMPLE 1
300 ml of THF are initially introduced at room temperature, and 84.7 g of potassium tert-butoxide are added with stirring 76.0 g of 2,2,2-trifluoroethanol are added dropwise to this reaction mixture, with the temperature being kept below 35° C.
When the addition is complete, stirring is continued, and 29.6 g of 5-bromo-2-chlorobenzoic acid are subsequently introduced.
After the subsequent addition of 27.3 g of copper(I) bromide, the reaction mixture is heated to reflux.
After 43 hours, the reaction mixture is cooled to 5° C. and allowed to run into dilute hydrochloric acid at 5° C.
The organic phase is separated from the aqueous phase,.
and the solvent is distilled off, during which the product precipitates.
100 ml of water are added to the residue and then filtered.
For purification, the crude product is taken up in MTB ether (methyl tert-butyl ether).
Undissolved components are separated off by filtration through neutral aluminium oxide, and the solvent is subsequently removed.
Recrystallisation from an ethanol/water mixture gives 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid in a yield of 45percent.
Melting point: 120-122° C., purity>98percent (HPLC).
Reference: [1] Patent: US2003/176721, 2003, A1,
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Reference: [1] Chinese Journal of Chemistry, 2011, vol. 29, # 6, p. 1192 - 1198
[2] Journal of the Indian Chemical Society, 1980, vol. 57, # 6, p. 640 - 642
[3] RSC Advances, 2018, vol. 8, # 12, p. 6306 - 6314
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YieldReaction ConditionsOperation in experiment
98% With borane dimethyl sulfide complex In tetrahydrofuran at 0 - 23℃; for 14 h; To a solution of 5-bromo-2-chlorobenzoic acid (5 g, 21 .23 mmol), in tetrahydrofuran (THF)(10 mL), 10 M borane-methyl sulfide complex (2.123 mL, 21.23 mmol) was added at 0°C.The reaction was then warmed to 23°C and stirred for 14h. The reaction mixture was cooled and additional 10 M borane-methyl sulfide complex (1 .062 mL, 10.62 mmol) was added to the reaction mixture. Afterwards, the reaction was cooled on an ice water bath and methanol (2.00 mL) was added slowly. When most of the bubbling ceased the volatile solvents wereremoved in vacuo and the residue was dissolved in EtOAc (1 OmI) and washed with saturated aq. NaHCO3. The aqueous layer was back extracted with EtOAc (50m1) and the combined EtOAc layers were washed with water (5m1) and saturated aq. NaCI, dried with Na2SO4 and concentrated to afford the title compound. (4.62 g, 98percent yield) 1H NMR (400 MHz, METHANOL-d4) 3 7.70 (5, 1H), 7.40 (d, J=8.28 Hz, 1H), 7.28 (d, J=8.53 Hz, 1H), 4.66(5, 2H)
97%
Stage #1: With sodium tetrahydroborate; iodine In tetrahydrofuran for 18 h; Reflux
Stage #2: With sodium hydrogensulfite In ethyl acetate
Intermediate 1: Preparation of (ZR^R^R^-y^-^-Z-Cacetoxymethyli-i-iS- (bromomethyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetateStep 1: Preparation of (5-bromo-2-chlorophenyl) methanol 5-bromo-2-chlorobenzoic acid (20 g, 84.92 mmol) in dry THF (50 mL) was added to a solution of sodium borohydride (8 g, 212.34 mmol) in dry THF (128 mL) in 15 min at r.t. To the resulting reaction mixture a solution of Iodine (26.85 g, 106.15 mmol) in dry THF (170 mL) was added in another 15 min. Stirring was continued till the Iodine color disappeared after which the reaction mixture was heated to reflux temperature for 18 h. After completion of the reaction as confirmed by TLC, volatiles were evaporated in vacuo. The residue obtained was dissolved in ethyl acetate (200 mL), washed with a saturated solution of NaHS03 (200 mL) and brine (200 mL) successively. The organic layer was dried over Na2S04 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 3: 7 Ethyl acetate: Pet. Ether) to afford the title compound ( 18.3 g, 97 percent).ESIMS (m/z): 222.8 (M+l)
97% With sodium tetrahydroborate; iodine In tetrahydrofuran for 18 h; Reflux Step 1: Preparation of (5-bromo-2-chlorophenyl) methanol 5-bromo-2-chlorobenzoic acid (20 g, 84.92 mmol) in dry THF (50 mL) was added to a solution of sodium borohydride (8 g, 212.34 mmol) in dry THF (128 mL) in 15 min at r.t. To the resulting reaction mixture a solution of Iodine (26.85 g, 106.15 mmol) in dry THF (170 mL) was added in another 15 min. Stirring was continued till the Iodine color disappeared after which the reaction mixture was heated to reflux temperature for 18 h. After completion of the reaction as confirmed by TLC, volatiles were evaporated in vacuo. The residue obtained was dissolved in ethyl acetate (200 mL), washed with a saturated solution of NaHS03 (200 mL) and brine (200 mL) successively. The organic layer was dried over Na2S04 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 3: 7 Ethyl acetate: Pet. Ether) to afford the title compound (18.3 g, 97 percent). ESIMS (m/z): 222.8 (M+l)
97%
Stage #1: With sodium tetrahydroborate In tetrahydrofuran at 20℃; for 0.25 h;
Stage #2: With iodine In tetrahydrofuran for 18.25 h; Reflux
Step 1:
Preparation of (5-bromo-2-chlorophenyl) methanol
5-bromo-2-chlorobenzoic acid (20 g, 84.92 mmol) in dry THF (50 mL) was added to a solution of sodium borohydride (8 g, 212.34 mmol) in dry THF (128 mL) in 15 min at r.t.
To the resulting reaction mixture a solution of Iodine (26.85 g, 106.15 mmol) in dry THF (170 mL) was added in another 15 min.
Stirring was continued till the Iodine color disappeared after which the reaction mixture was heated to reflux temperature for 18 h.
After completion of the reaction as confirmed by TLC, volatiles were evaporated in vacuo.
The residue obtained was dissolved in ethyl acetate (200 mL), washed with a saturated solution of NaHSO3 (200 mL) and brine (200 mL) successively.
The organic layer was dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 3: 7 Ethyl acetate: Pet.
Ether) to afford the title compound (18.3 g, 97 percent).
ESIMS (m/z): 222.8 (M+1)
3.6 g With dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 5 h; Inert atmosphere 2-Chloro-5-bromobenzoic acid (4.0 g, 0.0170 mol) was dissolved in anhydrous tetrahydrofuran (24 ml) Argon gas was added dropwise dimethyl sulfide borane (8.7ml, 0.0849mmol) at 0°C, After 5 hours at room temperature, TLC (thin layer chromatography) to complete the reaction, ice-water bath, slowly dropping water, Extracted with ethyl acetate and dried to give 3.6 g of a white solid, which was taken directly to the next step.

Reference: [1] Journal of Organic Chemistry, 2006, vol. 71, # 4, p. 1711 - 1714
[2] Patent: WO2018/109648, 2018, A1, . Location in patent: Page/Page column 96
[3] Patent: WO2012/172566, 2012, A2, . Location in patent: Page/Page column 52
[4] Patent: WO2013/38429, 2013, A2, . Location in patent: Page/Page column 48
[5] Patent: EP2755722, 2017, B1, . Location in patent: Paragraph 0105
[6] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 11, p. 3420 - 3425
[7] Patent: WO2016/202253, 2016, A1, . Location in patent: Page/Page column 378; 379
[8] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 14, p. 1903 - 1906
[9] Patent: EP1216980, 2002, A1,
[10] Patent: EP1394147, 2004, A1, . Location in patent: Page 85
[11] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 6, p. 2178 - 2194
[12] Patent: WO2010/147430, 2010, A2, . Location in patent: Page/Page column 51
[13] Patent: US2011/251247, 2011, A1,
[14] Patent: WO2011/159067, 2011, A2, . Location in patent: Page/Page column 49-50
[15] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 14, p. 2744 - 2748
[16] Patent: WO2016/22742, 2016, A1, . Location in patent: Page/Page column 205
[17] Patent: CN103772449, 2017, B, . Location in patent: Paragraph 0033; 0058-0060
[18] Patent: CN107556276, 2018, A, . Location in patent: Paragraph 0068-0071
[19] Patent: US6489487, 2002, B1,
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  • [ 189628-37-3 ]
Reference: [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 10, p. 2468 - 2485
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 14, p. 2744 - 2748
[3] Patent: WO2018/29611, 2018, A1,
[4] Patent: CN107556276, 2018, A,
[5] Patent: WO2007/136116, 2007, A2,
  • 18
  • [ 21739-92-4 ]
  • [ 103-73-1 ]
  • [ 461432-22-4 ]
YieldReaction ConditionsOperation in experiment
70%
Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 3 h;
Stage #2: With aluminum (III) chloride In dichloromethane at 4 - 5℃; for 1 h;
Add 5-bromo-2-chlorobenzoic acid (20.0 g,0.085mol) to a solution of 2.0 M oxalyl chloride in dichloromethane (50 ml, 0.1 mol), stir to a suspension, then add 8 drops of DMF solution with bubbles After the reaction was carried out for 3 hours, the reaction was substantially complete, and thesolvent was evaporated on a rotary evaporator, then 15 ml of dichloromethane was added and the solvent was evaporated.After spin-drying, add 30 ml of dichloromethane,stir, cool to 0-5 ° C, add phenylethyl ether (10.9 g, 0.089 mol), add anhydrous aluminum trichloride (12.5g,0.093mol) inbatches, control temperature is not After more than 5 ° C, after the addition is completed, stirring is continued at 4 ° C for 1 h. The reaction is almost complete by TLC. Thereaction mixture is quenched on ice-water mixture. The organic phase is separated, and the aqueous phase is extracted with dichloromethane. The organic phase was washed twice with 1 mol/L hydrochloric acid, and washed once with water. Wash twice with /L NaOH solution and wash twice with saturated sodium chloride. Dry over anhydrous sodium sulfate. Filter by suction and spin dry to give a white solid.Recrystallization from absolute ethanol gave 20.2 g (70.0percent) of white solid.
178 g
Stage #1: With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 25 - 40℃; for 4 h;
Stage #2: With aluminum (III) chloride In dichloromethane at 5 - 30℃; for 0.166667 h;
Stage #3: at 25 - 30℃; for 10 h;
Thionyl chloride (194.78 ml) was slowly added to a mixture of 5-bromo-2-chlorobenzoic acid compound of formula-2 (200 gms), dichloromethane (1000 ml) and dimethylformamide (1 ml) at 25-30° C.
Heated the reaction mixture to 35-40° C. and stirred for 4 hrs at the same temperature.
Distilled off the solvent completely from the reaction mixture under reduced pressure.
Dichloromethane (1600 ml) was added to the obtained compound at 25-30° C. and stirred for 20 mins at the same temperature.
Cooled the reaction mixture to 5-10° C. and stirred for 15 mins at the same temperature.
Aluminium chloride (110.9 gms) was slowly added to the reaction mixture at 5-10° C., the temperature of the reaction mixture was raised to 25-30° C. and stirred for 10 mins at the same temperature.
Phenetole (103.5 gms) was slowly added to the reaction mixture at 25-30° C. and stirred for 10 hrs at the same temperature.
The reaction mixture was poured into chilled hydrochloric acid solution (1000 ml of hydrochloric acid in 1000 gms of ice) at 25-30° C. and stirred for 20 mins at the same temperature.
Separated the both organic and aqueous layers, the organic layer was washed with 5percent aqueous sodium bicarbonate solution followed by with 10percent aqueous sodium chloride solution.
Distilled off the solvent completely from the organic layer under reduced pressure.
Methanol (400 ml) was added to the obtained compound at 55-60° C. and stirred for 45 mins.
Cooled the reaction mixture to 0-5° C. and stirred for 2 hrs at the same temperature.
Filtered the precipitated solid, washed with methanol.
Methanol (500 ml) was added to the wet solid, heated to 65-70° C. and stirred for 1 hr 30 mins at the same temperature.
Cooled the reaction mixture to 25-30° C., then to 0-5° C. and stirred for 3 hrs at 0-5° C.
Filtered the precipitated solid, washed with methanol and then dried to get title compound.
Yield: 178 gms; Melting range: 68-72° C.; Purity by HPLC: 98.8percent.
96 g
Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 25 - 30℃; for 15 h;
Stage #2: With aluminum (III) chloride In dichloromethane at 0 - 10℃; for 2 h;
Example 2
Preparation of (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone
5-Bromo-2-chloro benzoic acid (100 g) was dissolved in dichloromethane (200 mL) to obtain a solution. N,N-Dimethylformamide (1 mL) and oxalyl chloride (91.6 g) were added to the reaction mixture, and then the mixture was stirred for 15 hours at 25° C. to 30° C.
The reaction mixture was concentrated under reduced pressure at 40° C. to 45° C. Dichloromethane (80 mL) was added to the mixture, and then the mixture was cooled to 0° C. to 5° C. Ethyl phenyl ether (51.9 g) and aluminum chloride (64 g) were added to the mixture, and then the mixture was stirred for 2 hours at 0° C. to 10° C.
The reaction mixture was poured into chilled water (600 mL) maintained at 0° C. to 5° C., and then stirred for 60 minutes.
Deionized water (200 mL) and dichloromethane (350 mL) were added to the mixture, and then the layers were separated.
The aqueous layer was extracted with dichloromethane (350 mL).
The combined organic layers were washed with aqueous hydrochloric acid (1 L, 100 mL hydrochloric acid in 900 mL deionized water), an aqueous sodium hydroxide solution (4percent, 1 L), and an aqueous sodium chloride solution (20percent, 1 L), successively.
The organic layer was concentrated under reduced pressure to obtain an oily residue (115 g).
Ethanol (250 mL) was added to the oily residue, then the mixture was stirred for 5 minutes, then deionized water (100 mL) was added to the mixture, and then the mixture was stirred for 60 minutes at 20° C. to 25° C.
The mixture was filtered, and the wet solid obtained was washed with a mixture of deionized water (120 mL) and ethanol (60 mL).
Ethanol (250 mL) was added to the wet solid and the slurry obtained was stirred for 5 minutes.
Deionized water (100 mL) was added to the mixture over 20 minutes, and then the mixture was stirred for 60 minutes at 20° C. to 25° C.
The solid was filtered, then washed with a mixture of water (120 mL) and ethanol (60 mL) and then dried under reduced pressure at 40° C. to 45° C. for 12 hours to 15 hours to afford the title compound.
Reference: [1] Patent: CN108218928, 2018, A, . Location in patent: Paragraph 0176; 0177; 0178
[2] Patent: US2013/23486, 2013, A1, . Location in patent: Paragraph 0088
[3] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 21, p. 6282 - 6291
[4] Patent: US2017/29398, 2017, A1, . Location in patent: Paragraph 0075-0076
[5] Patent: US2017/342100, 2017, A1, . Location in patent: Paragraph 0129
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YieldReaction ConditionsOperation in experiment
92%
Stage #1: With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 10 - 30℃;
Stage #2: With aluminum (III) chloride In dichloromethane for 1 h; Cooling with ice
Step 1:
(5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone
To a mixture of 5-bromo-2-chlorobenzoic acid (15 g, 63.7 mmol) in DCM (50 mL) was added oxalyl chloride (8.1 mL, 95.6 mmol) and DMF (0.5 mL).
The resulted mixture was stirred at room temperature for overnight and then the solvent was evaporated under vacuum.
The residue was dissolved in DCM (30 mL), and added AlCl3 (10.2 g, 95.6 mmol) in small portions under ice-bath.
The mixture was stirred under ice-bath for 1 h, and then poured into ice water (100 g) to quench the reaction.
The mixture was extracted with ethyl acetate (100*2), the organic layer was washed with NaOH aqueous solution (1 M, 100*2), H2O and brine, dried over sodium sulfate, filtered and concentrated.
The residue was purified by recrystallization using ethanol to afford (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone (20 g, yield: 92percent) as a white solid.
Reference: [1] Patent: US2017/37038, 2017, A1, . Location in patent: Paragraph 0096; 0336; 0337
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[2] Patent: US6515117, 2003, B2,
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[2] Patent: US2014/51648, 2014, A1,
[3] Patent: WO2016/178148, 2016, A1,
[4] Patent: CN103739581, 2016, B,
[5] Patent: US2017/247356, 2017, A1,
[6] Patent: CN106928040, 2017, A,
[7] Patent: CN106316803, 2017, A,
[8] Patent: CN107417515, 2017, A,
[9] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 14, p. 3947 - 3952
[10] Patent: WO2012/25857, 2012, A1,
[11] Patent: WO2009/26537, 2009, A1,
[12] Patent: WO2010/9243, 2010, A1,
[13] Patent: CN108675976, 2018, A,
[14] Patent: CN108675976, 2018, A,
[15] Patent: CN108752184, 2018, A,
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[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 4, p. 1236 - 1251
[3] Patent: US2015/191502, 2015, A1,
[4] Patent: EP2891654, 2015, A1,
[5] Patent: KR2015/81220, 2015, A,
[6] Patent: US2017/247356, 2017, A1,
[7] Patent: CN108218928, 2018, A,
[8] Patent: CN108285439, 2018, A,
[9] Patent: WO2012/25857, 2012, A1,
[10] Patent: WO2009/26537, 2009, A1,
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[2] Patent: CN108675976, 2018, A,
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