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[ CAS No. 348-61-8 ] {[proInfo.proName]}

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Chemical Structure| 348-61-8
Chemical Structure| 348-61-8
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Product Details of [ 348-61-8 ]

CAS No. :348-61-8 MDL No. :MFCD00000304
Formula : C6H3BrF2 Boiling Point : -
Linear Structure Formula :- InChI Key :YMQPKONILWWJQG-UHFFFAOYSA-N
M.W : 192.99 Pubchem ID :67675
Synonyms :

Calculated chemistry of [ 348-61-8 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 34.06
TPSA : 0.0 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.27 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.11
Log Po/w (XLOGP3) : 3.11
Log Po/w (WLOGP) : 3.57
Log Po/w (MLOGP) : 3.91
Log Po/w (SILICOS-IT) : 3.38
Consensus Log Po/w : 3.21

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.49
Solubility : 0.0626 mg/ml ; 0.000324 mol/l
Class : Soluble
Log S (Ali) : -2.78
Solubility : 0.321 mg/ml ; 0.00167 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.81
Solubility : 0.0298 mg/ml ; 0.000155 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.44

Safety of [ 348-61-8 ]

Signal Word:Danger Class:3
Precautionary Statements:P210-P233-P240-P241-P242-P243-P261-P264-P270-P271-P272-P273-P280-P301+P312+P330-P303+P361+P353-P304+P340+P312-P333+P313-P370+P378-P391-P403+P235-P501 UN#:1993
Hazard Statements:H225-H302+H332-H315-H317-H411 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 348-61-8 ]

* 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 [ 348-61-8 ]
  • Downstream synthetic route of [ 348-61-8 ]

[ 348-61-8 ] Synthesis Path-Upstream   1~25

  • 1
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YieldReaction ConditionsOperation in experiment
0.06 mmol at 0 - 25℃; Cooling with ice General procedure: A FEP or PFA reactor equipped with a Teflon-lined magnetic stir bar and connected to a gas-washing bottle was charged with substituted benzene (0.95–1.10 mmol), 1,1,1,3,3-pentafluorobutane (1–2 mL per mmol of C6H5R), and BF3 · Et2O (1.3–1.5 mmol per mmol of C6H5R). The mixture was stirred for 10–15 min at 0–5°C (ice bath), and XeF2 (1.2–1.3 mmol per mmol of C6H5R) was added in portions. After addition of each portion, the mixture was stirred for 3–5 min at 22–25°C and cooled again. When the addition was complete the dark solution was stirred for 15–30 min at 22–25°C, 10percent aqueous KHCO3 was added, and the upper organic layer was separated, passed through a short column charged with silica gel (40–60 μm), and dried over MgSO4. The solution was analyzed by 19F NMR and GC/MS. The main products are given in table, and the others are listed below (GC/MS data).
Reference: [1] Russian Journal of Organic Chemistry, 2016, vol. 52, # 10, p. 1400 - 1407[2] Zh. Org. Khim., 2016, vol. 52, # 10, p. 1412 - 1419,8
  • 2
  • [ 108-86-1 ]
  • [ 1072-85-1 ]
  • [ 399-94-0 ]
  • [ 1073-06-9 ]
  • [ 348-61-8 ]
  • [ 460-00-4 ]
YieldReaction ConditionsOperation in experiment
0.06 mmol at 0 - 25℃; Cooling with ice General procedure: A FEP or PFA reactor equipped with a Teflon-lined magnetic stir bar and connected to a gas-washing bottle was charged with substituted benzene (0.95–1.10 mmol), 1,1,1,3,3-pentafluorobutane (1–2 mL per mmol of C6H5R), and BF3 · Et2O (1.3–1.5 mmol per mmol of C6H5R). The mixture was stirred for 10–15 min at 0–5°C (ice bath), and XeF2 (1.2–1.3 mmol per mmol of C6H5R) was added in portions. After addition of each portion, the mixture was stirred for 3–5 min at 22–25°C and cooled again. When the addition was complete the dark solution was stirred for 15–30 min at 22–25°C, 10percent aqueous KHCO3 was added, and the upper organic layer was separated, passed through a short column charged with silica gel (40–60 μm), and dried over MgSO4. The solution was analyzed by 19F NMR and GC/MS. The main products are given in table, and the others are listed below (GC/MS data).
Reference: [1] Russian Journal of Organic Chemistry, 2016, vol. 52, # 10, p. 1400 - 1407[2] Zh. Org. Khim., 2016, vol. 52, # 10, p. 1412 - 1419,8
  • 3
  • [ 348-61-8 ]
  • [ 2105-94-4 ]
  • [ 112204-58-7 ]
Reference: [1] Synlett, 2009, # 4, p. 633 - 637
  • 4
  • [ 367-11-3 ]
  • [ 348-61-8 ]
  • [ 64695-78-9 ]
  • [ 128259-74-5 ]
Reference: [1] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 393 - 406
  • 5
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  • [ 64695-82-5 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 1977, vol. 42, # 6, p. 2001 - 2017
  • 6
  • [ 348-61-8 ]
  • [ 75-36-5 ]
  • [ 64695-84-7 ]
Reference: [1] Patent: EP342849, 1990, A3,
  • 7
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  • [ 64695-84-7 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 1977, vol. 42, # 6, p. 2001 - 2017
  • 8
  • [ 348-61-8 ]
  • [ 64248-58-4 ]
Reference: [1] Molecular Crystals and Liquid Crystals Science and Technology Section A: Molecular Crystals and Liquid Crystals, 2002, vol. 373, p. 17 - 24
  • 9
  • [ 124-38-9 ]
  • [ 348-61-8 ]
  • [ 455-86-7 ]
Reference: [1] Molecular Crystals and Liquid Crystals Science and Technology Section A: Molecular Crystals and Liquid Crystals, 2000, vol. 348, p. 153 - 165
  • 10
  • [ 75-29-6 ]
  • [ 348-61-8 ]
  • [ 68-12-2 ]
  • [ 34036-07-2 ]
YieldReaction ConditionsOperation in experiment
86%
Stage #1: With iodine; magnesium In tetrahydrofuran at 20 - 40℃; for 5.66667 h; Inert atmosphere
Stage #2: at 0 - 10℃;
Stage #3: at 0 - 10℃; for 0.666667 h;
5L four-necked flask, mechanical stirring, nitrogen protection, followed by adding magnesium strips, 400g iodine granules in tetrahydrofuran, further, 41.7 g of 2-chloropropane was added at room temperature, 10min after the addition, temperature up to 40 deg. C, cooling, 30-40 ° C drop with a solution of 2-chloropropane, 4.5h dropwise additon is completed, insulation 1h, basically no magnesium. Cooling, a solution of 3,4-difluorobromobenzene (654 g of 3,4-difluorobromobenzene in 700 g of tetrahydrofuran) was dropwise added at 0 to 10 ° C, and the addition was completed in 50 minutes. Insulation reaction, can be done at room temperature. Reaction is completed, cooling, a solution of DMF (291.3 g of DMF in 300 g of tetrahydrofuran) was added dropwise at 0-10 ° C over 40 min. The temperature below 10 deg. C, dropping 700g of water, and then dropping concentrated hydrochloric acid to adjust pH to about 4, about 840g hydrochloric acid, phase separation, the lower aqueous phase with 500g toluene extraction twice, combine the organic layer, washed once with 500 g of saturated saline solution, and washed once with 500 g of water. 65 deg. C pump vacuum concentration to no solvent, was crude, vacuum distillation, the purity of more than 99.5percent, 86percent yield.
Reference: [1] Patent: CN105859536, 2016, A, . Location in patent: Paragraph 0016; 0017
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  • [ 34036-07-2 ]
Reference: [1] Patent: US6462242, 2002, B1,
  • 12
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  • [ 68-12-2 ]
  • [ 34036-07-2 ]
Reference: [1] Molecular Crystals and Liquid Crystals, 2010, vol. 528, p. 138 - 146
  • 13
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  • [ 109-94-4 ]
  • [ 34036-07-2 ]
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Reference: [1] Journal of Fluorine Chemistry, 1996, vol. 78, # 2, p. 113 - 119
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  • [ 64695-79-0 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 1977, vol. 42, # 6, p. 2001 - 2017
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  • [ 182169-61-5 ]
  • [ 85312-59-0 ]
Reference: [1] Tetrahedron Letters, 1997, vol. 38, # 3, p. 439 - 442
  • 16
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  • [ 85312-59-0 ]
Reference: [1] Chemical Communications, 1997, # 14, p. 1309 - 1310
  • 17
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  • [ 79-10-7 ]
  • [ 112897-97-9 ]
Reference: [1] Russian Journal of Organic Chemistry, 1997, vol. 33, # 4, p. 563 - 564
  • 18
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  • [ 112897-97-9 ]
Reference: [1] Molecular Crystals and Liquid Crystals, 2010, vol. 528, p. 138 - 146
  • 19
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  • [ 2105-94-4 ]
  • [ 112204-58-7 ]
Reference: [1] Synlett, 2009, # 4, p. 633 - 637
  • 20
  • [ 348-61-8 ]
  • [ 68-12-2 ]
  • [ 360576-04-1 ]
YieldReaction ConditionsOperation in experiment
83%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.583333 h;
Stage #2: at -78℃; for 0.25 h;
Stage #3: With acetic acid In tetrahydrofuran; water at -78 - 20℃;
Dissolve aryl bromide (1.0 [EQ)] in dry THF (0.2 M) and cool the reaction to-78 °C under nitrogen. Add LDA (2.0 M in THF, 1.1 eq. ) dropwise over 15 minutes. Stir for 20 minutes after addition complete. Add DMF (1.2 eq. ) and stir [AT-78 °C] for 15 minutes. Add glacial acetic acid (4.0 [EQ)] followed immediately by water [(12X] acetic acid volume) and [WARM] the reaction to room temperature. Separate the phases and extract the aqueous phase with ethyl acetate twice. Wash the combined organic layers with dilute aqueous HC1, water and brine. Dry with sodium sulfate, filter and concentrate. Purify the resulting residue on silica gel, eluting with 0 to 5percent ethyl acetate in hexanes.; PREPARATION 16 6-Bromo-2,3-difluoro-benzaldehyde (83percent) Yellow [OIL.APOS;H] NMR [(CDC13) OL O.] 31 (t, [J= 1.] 4 Hz, 1H), 7.45 (ddd, J= 9.0, 4.1, 1.9 Hz, [1H),] 7.29 (td, [J=] 9.2, 8.0 Hz, [1H).]
52%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5 h;
Stage #2: at -78℃; for 0.25 h;
4-Bromo-l,2-difluorobenzene (5.00 g, 25.9 mmol) was dissolved in tetrahydrofuran (100 mL) and cooled to -78 °C. Lithium diisopropyl amide (1.8 M in tetrahydrofuran, 15.8 mL, 28.5 mmol) was added. After stirring at -78 °C for 30 min, N,N-dimethylformamide (2.28 g, 31.1 mmol) was added. After stirring at -78 °C for an additional 15 min, acetic acid (6 mL) and water (100 mL) was added and the mixture was warmed to RT. After extraction with ethyl acetate, the organic phase was washed with 1 M hydrochloride acid solution and brine, and dried over magnesium sulfate. Concentration in vacuo afforded the title compound (2.59 g, 52percent of theory). GC-MS (Method 2G): Rt = 3.28 min, MS (ESIPos): m/z = 221 [M+H]+ .
2.59 g
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5 h;
Stage #2: at -78℃; for 0.25 h;
4-Bromo-1,2-difluorobenzene (5.00 g, 25.9 mmol) was dissolved in tetrahydrofuran (100 mL) and cooled to -78° C. Lithium diisopropyl amide (1.8 M in tetrahydrofuran, 15.8 mL, 28.5 mmol) was added.
After stirring at -78° C. for 30 min, N,N-dimethylformamide (2.28 g, 31.1 mmol) was added.
After stirring at -78° C. for an additional 15 min, acetic acid (6 mL) and water (100 mL) was added and the mixture was warmed to RT.
After extraction with ethyl acetate, the organic phase was washed with 1 M hydrochloride acid solution and brine, and dried over magnesium sulfate.
Concentration in vacuo afforded the title compound (2.59 g, 52percent of theory).
GC-MS (Method 2G): Rt=3.28 min, MS (ESIPos): m/z=221 [M+H]+
Reference: [1] Patent: WO2004/9578, 2004, A2, . Location in patent: Page 40
[2] Patent: WO2015/67549, 2015, A1, . Location in patent: Page/Page column 122
[3] Patent: US2015/126449, 2015, A1, . Location in patent: Paragraph 0676 - 0678
[4] Patent: WO2009/108838, 2009, A1, . Location in patent: Page/Page column 67-68
  • 21
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YieldReaction ConditionsOperation in experiment
56% With hydrogenchloride; n-butyllithium; sodium sulfate In tetrahydrofuran; hexane; N,N-dimethyl-formamide Example 1
2-Bromo-5,6-difluorobenzaldehyde
A solution of 152 mmol of 2,2,6,6-tetramethylpiperidine and 152 mmol of n-butyllithium (1.6 M solution in n-hexane) in 280 ml of dry tetrahydrofuran is admixed with 145 mmol of 1-bromo-3,4-difluorobenzene at -75° C.
This temperature is maintained for 4 hours, and then 174 mmol of DMF are added dropwise.
The reaction mixture is then slowly thawed, hydrolyzed with water at -20° C., acidified using hydrochloric acid and extracted with tert-butyl methyl ether.
The combined organic extracts are washed with saturated sodium chloride solution and dried using sodium sulfate.
The solvent is removed under reduced pressure, and the raw product is purified by chromatography over silica gel (eluent: dichloromethane/n-heptane 1:1) and recrystallization from n-heptane, yielding 18 g (56percent) of 2-bromo-5,6-difluorobenzaldehyde in the form of slightly yellow crystals.-M.p.: 40-43.5° C.-1H-NMR (400 MHz, CDCl3/TMS): δ=10.31 (dd, 4J(HF)=2 Hz, 5J(HF)=1.5 Hz, 1 H, CHO), 7.45 (ddd, 3J(HH)=9 Hz, 4J(HF)=4 Hz, 5J(HF)=2 Hz, 1 H, Har), 7.28 (ddd, 3J(HH)=9 Hz, 3J(HF)=9 Hz, 4J(HF)=8 Hz, 1 H, Har).-19F-NMR (376.5 MHz, 1H broad-band decoupled, CDCl3/CFCl3): δ=-136.4 (d, 3J=19.2 Hz), -139.2 (d, 3J=19.2 Hz).
Reference: [1] Patent: US2001/50352, 2001, A1,
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Reference: [1] Patent: US2003/166628, 2003, A1,
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YieldReaction ConditionsOperation in experiment
217.3 g
Stage #1: With isopropylmagnesium bromide In toluene at 25 - 30℃; Inert atmosphere
Stage #2: With copper(I) bromide dimethylsulfide complex In tetrahydrofuran; toluene at -30 - 20℃; Inert atmosphere
Preparation of compound 3Under a nitrogen atmosphere, to a 5L four-necked round bottom flask was added 193g (1mol) of the compound (2), 0.88LAnhydrous toluene to a four-necked round-bottomed flask, and then slowly add 1.05L 1M i-PrMgBr anhydrous toluene solution to control the temperatureAt 25-30 ° C, 96.5 mL of anhydrous tetrahydrofuran was added dropwise to give compound (3) The crude product was used directly in the next reaction.Preparation of Compound 1In a nitrogen atmosphere, to a 5L four-necked round bottom flask was added the reaction solvent anhydrous toluene 1L and anhydrous tetrahydrofuran50 mL and then added with 2 g (0.01 mol) of CuBr-SMe2, 10.1 g (0.02 mol) of the chiral ligand and 178 g(1.2mol), the reaction temperature was -30 ° C, slowly dropping all the compounds prepared in the previous step (3) After completion of the dropwise addition of TLC monitoringShould end after 2 hours reaction, slowly raised to room temperature, continue the reaction, TLC monitoring reaction, the end of the reaction after 4 hours, the reaction endedAfter adding 1L saturated aqueous solution of ammonium chloride to quench the reaction, liquid separation, the aqueous phase was added ethyl acetate extraction 3 times each added 1L, mergeThe organic phase was concentrated under reduced pressure to give the crude compound (1). The crude product was purified by vacuum distillation (0.06 mm Hg)The yield of the product (1) was 217.3 g and the mass yield was 113percent (two steps). The purity of the product was 99.28percent by HPLC.
Reference: [1] Patent: CN106854158, 2017, A, . Location in patent: Paragraph 0033; 0034; 0035; 0036; 0037; 0038; 0039-0052
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  • [ 100-51-6 ]
  • [ 1036724-54-5 ]
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Reference: [1] Tetrahedron Letters, 2008, vol. 49, # 31, p. 4588 - 4590
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  • [ 1186334-63-3 ]
Reference: [1] Patent: WO2009/108838, 2009, A1,
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