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[ CAS No. 281652-58-2 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 281652-58-2
Chemical Structure| 281652-58-2
Chemical Structure| 281652-58-2
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Product Details of [ 281652-58-2 ]

CAS No. :281652-58-2 MDL No. :MFCD02628389
Formula : C7H3Cl2IO Boiling Point : -
Linear Structure Formula :- InChI Key :CRBYUOHFEZMJTE-UHFFFAOYSA-N
M.W : 300.91 Pubchem ID :4769302
Synonyms :

Calculated chemistry of [ 281652-58-2 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 54.35
TPSA : 17.07 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.44 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.32
Log Po/w (XLOGP3) : 3.8
Log Po/w (WLOGP) : 3.32
Log Po/w (MLOGP) : 3.5
Log Po/w (SILICOS-IT) : 3.94
Consensus Log Po/w : 3.38

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -4.44
Solubility : 0.011 mg/ml ; 0.0000365 mol/l
Class : Moderately soluble
Log S (Ali) : -3.85
Solubility : 0.0422 mg/ml ; 0.00014 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.52
Solubility : 0.00915 mg/ml ; 0.0000304 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.85

Safety of [ 281652-58-2 ]

Signal Word:Danger Class:8
Precautionary Statements:P280-P305+P351+P338-P310 UN#:1759
Hazard Statements:H314 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 281652-58-2 ]

* 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 [ 281652-58-2 ]
  • Downstream synthetic route of [ 281652-58-2 ]

[ 281652-58-2 ] Synthesis Path-Upstream   1~8

  • 1
  • [ 281652-58-2 ]
  • [ 462-06-6 ]
  • [ 915095-86-2 ]
YieldReaction ConditionsOperation in experiment
93.4% With aluminum (III) chloride In dichloromethane at -5℃; for 6 h; Equipped with a thermometer, constant pressure dropping funnel, drying tube 1000mL flask was added three DCM200mL, VIII (70.62g, 250mmol) ,was added 1 ml of DMF and, at room temperature was slowly added dropwise oxalyl chloride (23.4mL g, 275mmol), was added dropwise after the completion of 20 incubated 2h.After adding concentrated to remove the DCM, oxalyl chloride 200mL DCM dissolved chloride.Equipped with a thermometer, constant pressure dropping funnel, 1000mL three 26mL flask with a drying tube was added fluorobenzene, DCM200mL the system temperature was dropped to -5 deg.] C, graded added to the system aluminum trichloride (36.67g, 275mmol) , dropped acid chloride prepared raw reaction incubated 6h completed.System 40mL conc HCl + 400mL poured into ice water to quench the reaction, the DCM. The combined organic phases were washed until neutral sodium bicarbonate, once with saturated brine separation was washed with water, dried, and concentrated to give VII84.23g, yield 93.4percent.
105 g at 25℃; Inert atmosphere Oxalyl chloride (72 g, 0.56 moles) was added to a slurry of formula 5a (100 g, 0.35 moles) and a catalytic amount of N, N-dimethylformamide (5mL) in fluorobenzene (250 mL) over about 60 minutes at 15-25 °C under nitrogen atmosphere. The mixture was stirred at 21-25 °C. After completion of the reaction, the reaction mass was concentrated to remove excess oxalyl chloride. The obtained residue was diluted with fluorobenzene (125 mL) and cooled to 15-25 °C. Aluminum chloride (53.5 g, 0.40 moles) was added to this reaction mixture portion- wise while keeping the reaction mass temperature below 25 °C and maintaining it at same temperature to complete the reaction. After completion of reaction, the reaction mass was quenched into precooled dilute hydrochloric acid (5percent, 1700 mL, 0-5 °C) at 5-25 °C. After stirring for 60 minutes at 20-25 °C, the product was extracted with methylene chloride twice (first with 500 mL, then with 250 mL). The combined organic layers were washed with 10percent aqueous sodium hydroxide solution (250mL), water (500mL), and 10percent aqueous sodium chloride solution (250mL), sequentially. Thereafter, the organic layer was concentrated and the obtained residue was diluted with n-heptane (250mL) and stirred to precipitate formula 7a as a white solid (105 g).
42.1 g With aluminum (III) chloride In dichloromethane at 20℃; for 3 h; Cooling with ice 5-iodo-2-chlorobenzoic acid (33.895 g, 120 mmol) was added DCM (100 mL) DMF (0.175 g, 0.02 eq), Stir, Slowly add oxalyl chloride (12.3 ^, 1.2 called), After the drop is completed at room temperature reaction 21 , The solvent was removed by concentration under reduced pressure, Add DCM (lOOmL), Fluorobenzene (17.298 g, 1.5 eq) was added, Alcia was added to A1C13 (17.6 g, 1 leq) After adding the reaction at room temperature for 3h, After TLC detection reaction was completed, Ice bath slowly add water (100mL), 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, Plus isopropyl alcohol (lOOmL), Add water (lOOmL), Ice bath stirring crystallization 2h, Filter, The filter cake was washed with isopropanol / water (1: 1) mixed solution (20 mL) Dried to give 42.1 g of an off-white solid of compound Vb, Yield: 97.3percent Purity: 99.17percent
Reference: [1] Patent: CN105399735, 2016, A, . Location in patent: Paragraph 0037; 0038; 0039
[2] Patent: US2006/258749, 2006, A1, . Location in patent: Page/Page column 21
[3] Organic Letters, 2014, vol. 16, # 16, p. 4090 - 4093
[4] Patent: WO2015/101916, 2015, A1, . Location in patent: Page/Page column 18; 19
[5] Patent: CN106928040, 2017, A, . Location in patent: Paragraph 0038-0039
  • 2
  • [ 281652-58-2 ]
  • [ 915095-94-2 ]
Reference: [1] Organic Letters, 2014, vol. 16, # 16, p. 4090 - 4093
[2] Patent: CN105399735, 2016, A,
  • 3
  • [ 281652-58-2 ]
  • [ 915095-87-3 ]
Reference: [1] Organic Letters, 2014, vol. 16, # 16, p. 4090 - 4093
[2] Patent: WO2015/101916, 2015, A1,
[3] Patent: CN105399735, 2016, A,
  • 4
  • [ 281652-58-2 ]
  • [ 103-73-1 ]
  • [ 1103738-29-9 ]
YieldReaction ConditionsOperation in experiment
67%
Stage #1: With aluminum (III) chloride In dichloromethane at -5 - 15℃;
Stage #2: at 25 - 30℃; for 26 h;
Preparation of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene
To a 250 mL of 4-necked flask equipped with an internal thermometer and a condenser was added ethoxybenzene (6.4 g, 52.5 mmol) and dichloromethane (19.2 mL) and the mixture was cooled to -5° C. Aluminum (III) chloride (7.4 g, 55 mmol) was added over 1 h while maintaining the internal temperature below 0° C.
After the addition was completed, the mixture was stirred for 30 min at 0˜5° C., and a solution of 2-chloro-5-iodobenzoyl chloride (15.0 g, 50 mmol) in dichloromethane (21 mL) was added dropwise over 1 hour while maintaining the internal temperature below 5° C.
The mixture was stirred for another 1 hour at 0˜5° C. and warmed to 10˜15° C. Polymethylhydrosiloxane (PMHS) (15.0 g, 0.25 mol) was added dropwise while maintaining the internal temperature below 25° C.
After stirring for 10 hours at 25° C., additional PMHS (9.0 g, 0.15 mol) was added to the above mixture.
After stirring for another 16 hours at 30° C., the mixture was cooled to 5˜10° C. and ice water (50 mL) was added slowly dropwise over 1 hour with stirring.
The mixture was filtered and the filter cake was slurried with dichloromethane (100 mL) containing diatomite (20 g).
The mixture was filtered and the filter cake was washed with dichloromethane (2*50 mL).
The combined organic layers were washed with brine (100 mL).
After removal of the volatiles, the residue was dissolved in absolute ethanol (45 mL) and refluxed with mechanical stirring (100 RPM) and cooled to 0° C.
After stirring for another 16 h at 0˜5° C., the mixture was filtered and the filter cake was washed with pre-cooled (0˜5° C.) ethanol (2*5 mL), dried under vacuum at 40° C. for 12 h to give 14.2 g of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a white solid.
This solid was recrystallized from ethanol (42.6 mL) to give 12.5 g of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a white solid.
Yield, 67percent, HPLC purity, HPLC-0002: 99.5percent. 1H NMR (CDCl3, 400 MHz): δ 7.21˜7.29 (m, 3H), 7.11 (d, J=8.8 Hz, 2H,), 6.85 (d, J=8.8 Hz, 2H,), 3.99˜4.07 (m, 4H), 1.43 (t, J=7.2 Hz, 3H).
67%
Stage #1: With aluminum (III) chloride In dichloromethane at -3 - 5℃; for 0.5 h;
Stage #2: at 0 - 25℃; for 12 h;
Stage #3: at 30℃; for 16 h;
[0257] To a 250 mL of 4-necked flask equipped with an internal thermometer and a condenser was added ethoxybenzene (6.4 g, 52.5 mmol) and dichloromethane (19.2 mL) and the mixture was cooled to -5 °C. Aluminum (III) chloride (7.4 g, 55 mmol) was added over 1 h while maintaining the internal temperature below 0 °C. After the addition was completed, the mixture was stirred for 30 min at 0-5 °C, and a solution of 2-chloro-5-iodobenzoyl chloride (15.0 g, 50 mmol) in dichloromethane (21 mL) was added dropwise over 1 hour while maintaining the internal temperature below 5 °C. The mixture was stirred for another 1 hour at 0-5 °C and warmed to 10-15 °C. Polymethylhydrosiloxane (PMHS) (15.0 g, 0.25 mol) was added dropwise while maintaining the internal temperature below 25 °C. After stirring for 10 hours at 25 °C, additional PMHS (9.0 g, 0.15 mol) was added to the above mixture. After stirring for another 16 hours at 30 °C, the mixture was cooled to 5-10 °C and ice water (50 mL) was added slowly dropwise over 1 hour with stirring. The mixture was filtered and the filter cake was slurried with dichloromethane (100 mL) containing diatomite (20 g). The mixture was filtered and the filter cake was washed with dichloromethane (2x50 mL). The combined organic layers were washed with brine (100 mL). After removal of the volatiles, the residue was dissolved in absolute ethanol (45 mL) and refluxed with mechanical stirring (100 RPM) and cooled to 0 °C. After stirring for another 16 h at 0-5 °C, the mixture was filtered and the filter cake was washed with pre-cooled ( 0-5 °C) ethanol (2 x 5 mL), dried under vacuum at 40 °C for 12 h to give 14.2 g of l-chloro-2-(4-ethoxybenzyl)-4- iodobenzene as a white solid. This solid was recrystallized from ethanol (42.6 mL) to give 12.5 g of l-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a white solid. Yield, 67percent, purity: 99.5percent by HPLC Method EGT-M-0002. 1H NMR (CDC13, 400 MHz): δ 7.21-7.29 (m, 3H), 7.11(d, J=8.8 Hz, 2H,), 6.85 (d, J=8.8 Hz, 2H,), 3.99-4.07 (m, 4H), 1.43(t, J=7.2 Hz, 3H).
67%
Stage #1: With aluminum (III) chloride In dichloromethane at 0 - 5℃; for 2 h;
Stage #2: at 25 - 30℃; for 26 h;
To a 250 mL of 4-necked flask equipped with an internal thermometer and a condenser was added ethoxybenzene (6.4 g, 52.5 mmol) and dichloromethane (19.2 mL) and the mixture was cooled to -5 °C. Aluminum (III) chloride (7.4 g, 55 mmol) was added over 1 h while maintaining the internal temperature below 0 °C. After the addition was completed, the mixture was stirred for 30 min at 0-5 °C, and a solution of 2-chloro-5-iodobenzoyl chloride (15.0 g, 50 mmol) in dichloromethane (21 mL) was added dropwise over 1 hour while maintaining the internal temperature below 5 °C. The mixture was stirred for another 1 hour at 0-5 °C and warmed to 10-15 °C. Polymethylhydrosiloxane (PMHS) (15.0 g, 0.25 mol) was added dropwise while maintaining the internal temperature below 25 °C. After stirring for 10 hours at 25 °C, additional PMHS (9.0 g, 0.15 mol) was added to the above mixture. After stirring for another 16 hours at 30 °C, the mixture was cooled to 5-10 °C and ice water (50 mL) was added slowly dropwise over 1 hour with stirring. The mixture was filtered and the filter cake was slurried with dichloromethane (100 mL) containing diatomite (20 g). The mixture was filtered and the filter cake was washed with dichloromethane (2x50 mL). The combined organic layers were washed with brine (100 mL). After removal of the volatiles, the residue was dissolved in absolute ethanol (45 mL) and refluxed with mechanical stirring (100 RPM) and cooled to 0 °C. After stirring for another 16 h at 0-5 °C, the mixture was filtered and the filter cake was washed with pre-cooled ( 0-5 °C) ethanol (2 x 5 mL), dried under vacuum at 40 °C for 12 h to give 14.2 g of l-chloro-2-(4-ethoxybenzyl)-4- iodobenzene as a white solid. This solid was recrystallized from ethanol (42.6 mL) to give 12.5 g of l-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a white solid. Yield, 67percent, HPLC purity, HPLC-0002: 99.5percent. 1H NMR (CDC13, 400 MHz): δ 7.21-7.29 (m, 3H), 7.1 l(d, J=8.8 Hz, 2H,), 6.85 (d, J=8.8 Hz, 2H,), 3.99-4.07 (m, 4H), 1.43(t, J=7.2 Hz, 3H).
Reference: [1] Patent: US2013/267694, 2013, A1, . Location in patent: Page/Page column 0309-0310
[2] Patent: WO2013/152476, 2013, A1, . Location in patent: Paragraph 0257
[3] Patent: WO2013/152654, 2013, A1, . Location in patent: Paragraph 0269
  • 5
  • [ 281652-58-2 ]
  • [ 1103738-29-9 ]
Reference: [1] Patent: EP2332947, 2011, A1,
[2] Patent: EP2661256, 2018, B1,
  • 6
  • [ 281652-58-2 ]
  • [ 103-73-1 ]
  • [ 1103738-26-6 ]
YieldReaction ConditionsOperation in experiment
98.5% With aluminum (III) chloride In dichloromethane at -7 - 9℃; for 2.33333 h; A jacketed 2 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and pressure-equalized addition funnel with gas bubbler was charged with aluminum chloride (97.68 g, 0.733 mol, 1.04 equiv), dichloromethane (0.65 L, KF=0.003 wt percent water) and the suspension was set stirring under nitrogen and was cooled to about 6° C. Then ethoxybenzene (90 mL, 0.712 mol, 1.01 equiv) was added over 7 minutes keeping internal temperature below 9° C. The resulting orange solution was diluted with dichloromethane (75 mL) and was cooled to -7° C. Then a solution of 2-chloro-5-iodobenzoyl chloride (<0.706 mol) in 350 mL dichloromethane was added over 13 minutes keeping the internal temperature below +3° C. The reaction mixture was warmed slightly and held at +5° C. for 2 hours. HPLC analysis suggested the reaction was complete and the reaction was quenched into 450 mL pre-cooled (5° C.) 2N aq. HCl with stirring in a jacketed round bottom flask. This quench was done in portions over 10 min with internal temperature remaining below 28° C. The quenched biphasic mixture was stirred at 20° C. for 45 min and the lower organic phase was washed with 1N aq. HCl (200 mL), twice with saturated aq. sodium bicarbonate (200 mL per wash), and with saturated aq. sodium chloride (200 mL). The washed extract was concentrated on a rotary evaporator to afford crude (2-chloro-5-iodophenyl)(4-ethoxyphenyl)methanone as an off-white solid (268.93 g, 99.0 area percent by HPLC at 220 nm, 1.0 area percent regioisomer at 200 nm, 98.5 percent "as-is" yield).
72%
Stage #1: With aluminum (III) chloride In dichloromethane at 15 - 25℃; for 1 h; Inert atmosphere
Stage #2: at -5 - 20℃; for 6 h;
Under nitrogen atmosphere, 5.3 g of 2-chloro-5-iodobenzoyl chloride was dissolved in 30 mL of methylene chloride and added into a 100 mL reaction flask. 2.8 g of anhydrous aluminum trichloride was added, and the complexation reaction was carried out at 15-25 ° C. for 1 hour, cooled to -5-0 , 2.23g phenetidine was dissolved in 10mL dichloromethane slowly dropwise added, the control temperature <5 , after dropping temperature was raised to 15-20 reaction 6hrs, the reaction solution was slowly poured into 50mL 1mol / L dilute hydrochloric acid, the control temperature was controlled <10 , the layers were separated, the aqueous phase was extracted twice with 60mL of dichloromethane, the combined organic phase was washed successively with water, saturated sodium bicarbonate solution, saturated brine, anhydrous sodium sulfate Dried, filtered and concentrated under reduced pressure to give the crude product as a yellow-brown solid which was recrystallized from absolute ethanol to give 4.95 g of a white solid in 72percent yield.
Reference: [1] Patent: US2009/30198, 2009, A1, . Location in patent: Page/Page column 8-9
[2] Patent: CN106316803, 2017, A, . Location in patent: Paragraph 0017
[3] Patent: US2010/16422, 2010, A1, . Location in patent: Page/Page column 5
[4] Patent: EP2332947, 2011, A1, . Location in patent: Page/Page column 7-8
[5] Patent: EP2661256, 2018, B1, . Location in patent: Paragraph 0095
  • 7
  • [ 281652-58-2 ]
  • [ 1103738-26-6 ]
Reference: [1] Patent: CN106928040, 2017, A,
[2] Patent: CN106928040, 2017, A,
[3] Patent: CN106928040, 2017, A,
  • 8
  • [ 281652-58-2 ]
  • [ 1103738-30-2 ]
Reference: [1] Patent: EP2332947, 2011, A1,
[2] Patent: EP2661256, 2018, B1,
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