Structure of 426831-32-5
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CAS No. : | 426831-32-5 |
Formula : | C8H9FO2 |
M.W : | 156.15 |
SMILES Code : | COC1=C(CO)C=C(F)C=C1 |
MDL No. : | MFCD00671767 |
Boiling Point : | No data available |
InChI Key : | NJDNHGOIOZXFCB-UHFFFAOYSA-N |
Pubchem ID : | 22014996 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.25 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 39.02 |
TPSA ? Topological Polar Surface Area: Calculated from |
29.46 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.99 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.11 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.59 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.64 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.08 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.68 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.78 |
Solubility | 2.6 mg/ml ; 0.0166 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.32 |
Solubility | 7.44 mg/ml ; 0.0477 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.62 |
Solubility | 0.375 mg/ml ; 0.0024 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.46 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.31 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With thionyl chloride; at -78 - 20℃; | Neat [(5-FLUORO-2-METHOXY-PHENYL)-METHANOL] (19.587g, 1 equiv. ) was added [ TO NEAT SOC12 (42.2 ML, 4.6 EQUIV. ) AT-78C UNDER A NITROGEN ATMOSPHERE AND THE] solution was then allowed to warm to room temperature and stirred until evolution of gas had ceased. An equivalent volume of anhydrous toluene was added to the flask and the solution heated to [60C.] On cooling the reaction solution was poured onto ice water. The toluene layer was separated and dried (MgSO4) and the solvent removed under reduced pressure. The crude material was sublimed [(60-80C/0.] 05 [MBARR)] to give the title compound as a white solid (13.40 g, [61%). 1H No.] [(300MHZ,] CDCl3) : [No. ]3. 87 (s, 3H), 4.60 (s, 2H), 6. [79-7. 20] (m, [3H).] |
61% | With thionyl chloride; at -78 - 20℃; | Neat (5-Fluoro-2-methoxy-phenyl) -methanol (19. 587G, 1 equiv. ) was added to NEAT SOC12 (42.2 ML, 4.6 EQUIV. ) AT-78C UNDER A NITROGEN ATMOSPHERE AND THE SOLUTION was then allowed to warm to room temperature and stirred until evolution of gas had ceased. An equivalent volume of anhydrous toluene was added to the flask and the solution heated to 60C. On cooling the reaction solution was poured onto ice water. The toluene layer was separated and dried (MgS04) and the solvent removed under reduced pressure. The crude material was sublimed (60-80C/0. 05 mBarr) to give the title compound as a white solid (13.40 g, 61 %). 1H NMR (300MHZ, CDC13): 6 3.87 (s, 3H), 4.60 (s, 2H), 6.79-7. 20 (m, 3H). |
61% | Neat (5-Fluoro-2-methoxy-phenyl) -methanol (19.587g, 1 equiv. ) was added to neat SOC12 (42.2 mL, 4.6 equiv. ) at-78C under a nitrogen atmosphere and the solution was then allowed to warm to room temperature and stirred until evolution of gas had ceased. An equivalent volume of anhydrous toluene was added to the flask and the solution heated to 60C. On cooling the reaction solution was poured onto ice water. The toluene layer was separated and dried (MGS04) and the solvent removed under reduced pressure. The crude material was sublimed (60-80C/0. 05 mBarr) to give the title compound as a white solid (13.40 g, 61%). IH NMR (300MHZ, CDC13) : 5 3.87 (s, 3H), 4.60 (s, 2H), 6.79-7. 20 (m, 3H). |
61% | 5-fluoro-2-methoxybenzyl chloride; Neat (5-Fluoro-2-methoxy-phenyl)-methanol (19.587g, 1 equiv. ) is added to neat SOC12 (42.2 mL, 4.6 equiv. ) at-78C under a nitrogen atmosphere and the solution is then allowed to warm to room temperature and stirred until evolution of gas ceases. An equivalent volume of anhydrous toluene is added to the flask and the solution heated to 60C. On cooling, the reaction solution is poured onto ice water. The toluene layer is separated and dried (MgSO4) and the solvent removed under reduced pressure. The crude material is sublimed (60-80C/0. 05 mBarr) to give the title compound as a white solid (13.40 g, 61%). MW 174. 60 ; CsHgClFO ;'HNMR (CDCIs) : 3.87 (s, 3H), 4.60 (s, 2H), 6.79-7. 20 (m, 3H). | |
61% | With thionyl chloride; at -78 - 20℃;Neat (no solvent); | Neat (5-Fluoro-2-methoxy-phenyl) -methanol (19.587g, 1 equiv. ) was added to neat SOC12 (42.2 mL, 4.6 equiv. ) at-78C under a nitrogen atmosphere and the solution was then allowed to warm to room temperature and stirred until evolution of gas had ceased. An equivalent volume of anhydrous toluene was added to the flask and the solution heated to 60C. On cooling the reaction solution was poured onto ice water. The toluene layer was separated and dried (MgSO4) and the solvent removed under reduced pressure. The crude material was sublimed (60-80C/0. 05 mBarr) to give the title compound as a white solid (13.40 g, 61%).'H NMR (300MHz, CDC13) : S 3.87 (s, 3H), 4.60 (s, 2H), 6.79-7. 20 (m, 3H).; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium tetrahydroborate; In methanol; at -10 - 20℃; for 0.5h; | To a solution of 2-Methoxy-5-fluorobenzaldehyde (11.093g, 1 equiv.- available from Aldrich Chemical Company) in methanol at-10 C under nitrogen atmosphere was added NaBH4 (7.515g, 2.7 equiv. ) portionwise. The solution was allowed to warm to room temperature and after 30 minutes the reaction solvent was removed under reduced pressure and replaced with dichloromethane. This solution was poured onto ice water and further extracted with dichloromethane. The organic fractions were collected and dried [(MGS04)] and the solvent removed under reduced pressure to give the title compound as an oil (9.794g, [87%).'H] NMR [(300MHZ,] [CDC13)] : [6] 2. [58] (m, 1H), 3.81 (s, 3H), 4.63 (d, 2H, [J =] 6.3 Hz), 6.78 (dd, [1H,] J= 8.9 and 4.3 Hz), 6.94 (td, 1H, J = 8.5 and 3. 1Hz), 7.04 (dd, 1H, J = 8.7 and 3. 1Hz). |
87% | With sodium tetrahydroborate; In methanol; at -10 - 20℃; for 0.5h; | To a solution OF 2-METHOXY-5-FLUOROBENZALDEHYDE (11. 093g, 1 equiv.-available from Aldrich Chemical Company) in methanol at-10 C under nitrogen atmosphere was added NaBH4 (7. 515G, 2.7 equiv. ) portionwise. The solution was allowed to warm to room temperature and after 30 minutes the reaction solvent was removed under reduced pressure and replaced with dichloromethane. This solution was poured onto ice water and further extracted with dichloromethane. The organic fractions were collected and dried (MgS04) and the solvent removed under reduced pressure to give the title compound as an oil (9.794g, 87%). H NMR (300MHZ, CDC13) : 6 2.58 (m, 1H), 3.81 (s, 3H), 4.63 (d, 2H, J= 6.3 Hz), 6. 78 (dd, 1H, J= 8.9 and 4.3 Hz), 6.94 (td, 1H, J= 8.5 and 3. 1HZ), 7.04 (dd, 1H, J= 8. 7 AND 3. 1HZ). |
87% | With sodium tetrahydroborate; In methanol; at -10 - 20℃; for 0.5h; | To a solution of 2-Methoxy-5-fluorobenzaldehyde (11. 093g, 1 equiv. -available from Aldrich Chemical Company) in methanol at-10 C under nitrogen atmosphere was added NaBH4 (7. 515g, 2.7 equiv.) portionwise : The solution was allowed to warm to room temperature and after 30 minutes the reaction solvent was removed under reduced pressure and replaced with dichloromethane. This solution was poured onto ice water and further extracted with dichloromethane. The organic fractions were collected and dried (MGSO4) and the solvent removed under reduced pressure to give the title compound as an oil (9. 794g, 87%). H NMR (300MHZ, CDC13) : No. 2. 58 (m, 1H), 3. 81 (s, 3H), 4.63 (d, 2H, J= 6.3 Hz), 6.78 (dd, 1H, J= 8.9 and 4.3 Hz), 6.94 (td, 1H, J= 8.5 and 3. 1Hz), 7.04 (dd, 1H, J= 8. 7 AND 3. 1HZ). |
87% | To a solution of 2-Methoxy-5-fluorobenzaldehyde (11. 093g, 1 equiv.-available from Aldrich Chemical Company) in methanol at-10 C under nitrogen atmosphere was added NaBH4 (7.515g, 2.7 equiv. ) portionwise. The solution was allowed to warm to room temperature and after 30 minutes the reaction solvent was removed under reduced pressure and replaced with dichloromethane. This solution was poured onto ice water and further extracted with dichloromethane. The organic fractions were collected and dried (MgSO4) and the solvent removed under reduced pressure to give the title compound as an oil (9.794g, 87%).'H NMR (300MHz, CDC13) : S 2.58 (m, 1H), 3.81 (s, 3H), 4.63 (d, 2H, J = 6.3 Hz), 6.78 (dd, 1H, J = 8.9 and 4.3 Hz), 6.94 (td, 1H, J = 8. 5 and 3. lHz), 7.04 (dd, 1H, J= 8. 7 and 3. 1Hz). | |
52% | With sodium tetrahydroborate; In methanol; at -10 - 20℃; for 0.5h; | (5-Fluoro-2-methoxy-phenyl)-methanol To a solution of <strong>[19415-51-1]2-methoxy-5-fluorobenzaldehyde</strong> (11. 093g, 1 eq, available from Aldrich Chemical Company) in methanol at-10 C under nitrogen atmosphere is added NaBH4 (7. 515g, 2.7 equiv. ) portionwise. The solution is allowed to warm to room temperature and after 30 minutes the reaction solvent is removed under reduced pressure and replaced with dichloromethane. This solution is poured onto ice water and further extracted with dichloromethane. The organic fractions are collected and dried (MgS04) and the solvent removed under reduced pressure to give the title compound as an oil (9.794g, 87%). MW 156.16 ; CsH9F02 ;'H NMR (CDC13) : 2. 58 (m, 1H), 3.81 (s, 3H), 4.63 (d, 2H, 6.3 Hz), 6.78 (dd, 1H, 8. 9 Hz and 4.3 Hz), 6.94 (td, 1H, 8.5 Hz and 3.1 Hz), 7.04 (dd, 1H, 8.7 Hz and 3.1 Hz). |
With sodium tetrahydroborate; In ethanol; at 20℃; for 1h; | This intermediate is synthesised as follows: Add Sodium borohydride (540 mg, 13.95 mmol) in portions to a solution of 5-Fluoro-2- methoxy-benzaldehyde (2.15g, 13.94 mmol) in absolute EtOH (20 ml) and stir at room temperature. After lh, evaporate the solvent, dilute the residue in CH2Cl2 and treat with aqueous 3M HCI. Separate the phases, wash the organic one twice with H2O, dry over Na2S04 and concentrate at vacuum to obtain pure (5-Fluoro-2-methoxy-phenyl)-methanol as white solid. Add aqueous concentrated HBr (15 ml) to a solution of (5-Fluoro-2- methoxy-phenyl)-methanol (1.9g, 12.17 mmol) in CHC13 (10 ml) and stir at room temperature. After 1h, separate the phases, wash the aqueous one with CH2C12, combine organic phases, wash with H2O, dry over Na2SO4 and concentrate at vacuum to obtain a residue. Purify the residue by column chromatography on silica gel eluting with hexane to afford 2-Bromomethyl-4-fluoro-1-methoxy-benzene as white solid.'H-NMR (CDCl3, 200 MHz) : 8 7.06 (dd, J=3.0 and 8.6 Hz, 1H), 6.98 (m, 1H), 6.81 (dd, J= 4.4 and 9.0 Hz, 1H), 4.50 (s, 2H), 3.87 (s, 3H). | |
With lithium aluminium tetrahydride; In tetrahydrofuran; at 20 - 60℃; | To a suspension of LiAlH4 (1.2 g, 32 mmol) in dry THF (5 mL) was added the aldehyde (10 mmol) and the mixtures were stirred at room temperature for two hours. Mixtures with aldehydes as starting materials were put aside and the acids were heated at 60 C. overnight. To each mixture was added in consecutive order water (1.2 mL), 2 M aqueous NaOH (1.2 mL), and water (3.6 mL). The precipitate was filtered off and the solvent was removed under reduced pressure to yield the target products as oils. The title compound was prepared starting from <strong>[19415-51-1]5-fluoro-2-methoxybenzaldehyde</strong> and was obtained as a light red oil (94% yield). Fragmenting MS analysis supports the stated structure. Purity 97% (GC). 1H NMR (CDCl3) ?3.28 (s, 3 H), 4.64 (s, 2 H), 6.78 (m, 1 H), 6.93 (m, 1 H), 7.02 (m, 1 H). 13C NMR (CDCl3) ?55.73, 61.34, 110.83 (d, J=8.5 Hz), 114.22 (d, J=22.6Hz), 115.26 (d, J=23.3 Hz), 138.68 (d, J=6.4 Hz), 153.18 (d, J=2.1 Hz), 156.95 (d, J=238.8 Hz). | |
With sodium tetrahydroborate; In ethanol; at 0℃; for 1h; | A 100ml four-necked flask was charged with 5.0 g (32.4 mmol) of <strong>[19415-51-1]5-fluoro-2-methoxybenzaldehyde</strong> and 100ml of ethanol, and 1.23 g (32.4 mmol) of sodium borohydride was added thereto with stirring under ice-cooling.. Then, the mixture was stirred for 1 hour and allowed to stand at room temperature overnight.. After concentrating under reduced pressure, 50 ml of ethyl acetate and 50 ml of water were added to the residue, and the mixture was shaken and separated into layers.. The aqueous layer was extracted once again with 50 ml of ethyl acetate.. The ethyl acetate layers were combined, and washed with 50 ml of water followed by 50 ml of saturated brine.. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to obtain 5-fluoro-2-methoxybenzyl alcohol.1H-NMR (CDCl3) delta: 3.83 (s, 3H), 4.66 (d, 2H, J= 6.4Hz), 6.77-7.07 (m, 3H). | |
With methanol; sodium tetrahydroborate; at 20℃; for 18h; | Step 1: To 42 (1 eq, 17.1 mmol, 2.6 g) in MeOH (68 ml_) at room temperature, added NaBH4 {1.2 eq, 20.5 mmol, 775 mg) and the reaction mixture stirred 18h, then concentrated in vacuo. The crude residue was diluted with ethyl acetate, washed with 1 N aqueous HCI then brine, dried over sodium sulfate, and concentrated in vacuo to give 43 (2.8 g) as a pale yellow oil | |
a) Preparation of (5-fluoro-2-methoxy-phenyl)-methanolSodium borohydride (61 mg, 1.62 mmol) is added to a solution of 5-fluoro-2- methoxybenzaldehyde (1.0 g, 6.49 mmol) in MeOH (10 mL). After 1 hour, the reaction is poured in to 1 M aqueous HCI and extracted with DCM. The combined organic phases are dried (Na2SO4) , evaporated and purified by flash chromatography (0-100% EtOAc- isohexanes gradient elution) to afford (5-fluoro-2-methoxy-phenyl)-methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.4% | With ethyl o-phenylene phosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 96h; | A 25 ml round-bottomed flask was charged with 1.0 g (2.96 mmol) of 3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 508 mg (3.26 mmol) of <strong>[426831-32-5]5-fluoro-2-methoxybenzyl alcohol</strong>, 2.18 g (16.87 mmol) of diisopropylethylamine, 10 ml of dichloromethane and 889 mg (4.44 mmol) of EPPA, and the mixture was stirred at room temperature for about 4 days.. To the reaction mixture was added 10 ml of water, and the dichloromethane layer was separated.. The aqueous layer was extracted once again with 10 ml of dichloromethane, and then the organic layers were combined and washed with water (10 ml) followed by saturated brine (10 ml).. The mixture was dried over an anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (50 g, n-hexane-ethyl acetate 4: 1, V/V) to obtain 642 mg of the title compound (yield: 49.4%). IR (KBr): 2484, 1729, 1604, 1508, 1224, 1159, 1028, 823, 720, 555cm-1.1H-NMR (CDCl3) delta: 2.38-2.61 (m, 4H), 2.74-2.78 (m, 1H), 2.85-2.90 (m, 1H), 3.26-3.31 (m, 1H), 3.52 (s, 2H), 3.74 (s, 3H), 4.58 (d, 1H, J=11.2Hz), 6.75 (m, 1H), 6.86-6.96 (m, 5H), 7.09-7.12 (m, 3H), 7.23-7.26 (m, 2H). |
With 2-oxo-2-ethoxy-4,5-benzo-1,3,2-dioxaphospholane; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Cooling with ice; | General procedure: A cooled mixture of 12 (6.7 g, 20.0 mmol), 2-hydroxybenxyl alcohol (2.6 g, 20.0 mmol) and diisopropylethylamine (10.2 mL, 58.6 mmol) in CH2Cl2 (50 mL) was added ethyl o-phenylenephosphate (EPPA) (4.8 mL) in an ice bath. The mixture was stirred at room temperature for 60 min, and poured into EtOAc. The solution was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from diethyl ether to give 13a (6.9 g, 85%) as crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen bromide; In chloroform; water; at 20℃; for 1h; | This intermediate is synthesised as follows: Add Sodium borohydride (540 mg, 13.95 mmol) in portions to a solution of 5-Fluoro-2- methoxy-benzaldehyde (2.15g, 13.94 mmol) in absolute EtOH (20 ml) and stir at room temperature. After lh, evaporate the solvent, dilute the residue in CH2Cl2 and treat with aqueous 3M HCI. Separate the phases, wash the organic one twice with H2O, dry over Na2S04 and concentrate at vacuum to obtain pure (5-Fluoro-2-methoxy-phenyl)-methanol as white solid. Add aqueous concentrated HBr (15 ml) to a solution of (5-Fluoro-2- methoxy-phenyl)-methanol (1.9g, 12.17 mmol) in CHC13 (10 ml) and stir at room temperature. After 1h, separate the phases, wash the aqueous one with CH2C12, combine organic phases, wash with H2O, dry over Na2SO4 and concentrate at vacuum to obtain a residue. Purify the residue by column chromatography on silica gel eluting with hexane to afford 2-Bromomethyl-4-fluoro-1-methoxy-benzene as white solid.'H-NMR (CDCl3, 200 MHz) : 8 7.06 (dd, J=3.0 and 8.6 Hz, 1H), 6.98 (m, 1H), 6.81 (dd, J= 4.4 and 9.0 Hz, 1H), 4.50 (s, 2H), 3.87 (s, 3H). | |
With hydrogen bromide; In chloroform; at 20℃; for 2h; | Step 2: To 43 (1 eq, 17.9 mmol, 2.8 g) in CHCU (18 ml_) at room temperature, added HBr (22 mL) and the reaction mixture was stirred 2h, then diluted with dichloromethan, washed with water then brine, dried over sodium sulfate, and concentrated in vacuo to give 44 (3.3 g) as an off-white solid. | |
With phosphorus tribromide; In dichloromethane; for 0.5h; | b) Preparation of 2-bromomethyl-4-fluoro-1-methoxy-benzenePhosphorus tribromide (0.312 mL, 3.28 mmol) is added to a solution of (5-fluoro-2- methoxy-phenyl)-methanol (1.03 g, 6.56 mmol) in DCM (10 mL). After 30 minutes, the reaction mixture is poured directly on to a silica gel column and eluted with DCM to afford 2-bromomethyl-4-fluoro-1-methoxy-benzene. |
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