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CAS No. : | 877151-43-4 | MDL No. : | MFCD22571667 |
Formula : | C10H8FNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LVGDEACFPFFUFB-UHFFFAOYSA-N |
M.W : | 193.17 | Pubchem ID : | 57949316 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.2 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 47.36 |
TPSA : | 50.09 Ų |
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) : | -6.09 cm/s |
Log Po/w (iLOGP) : | 2.09 |
Log Po/w (XLOGP3) : | 1.96 |
Log Po/w (WLOGP) : | 2.21 |
Log Po/w (MLOGP) : | 2.0 |
Log Po/w (SILICOS-IT) : | 2.6 |
Consensus Log Po/w : | 2.17 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.46 |
Solubility : | 0.673 mg/ml ; 0.00349 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.64 |
Solubility : | 0.446 mg/ml ; 0.00231 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.23 |
Solubility : | 0.114 mg/ml ; 0.000589 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.02 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P261-P264-P270-P271-P280-P302+P352-P304+P340-P310-P330-P361-P403+P233-P405-P501 | UN#: | 2811 |
Hazard Statements: | H301-H311-H331 | Packing Group: | Ⅲ |
GHS Pictogram: |
* 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 |
---|---|---|
Multi-step reaction with 3 steps 1.1: sodium nitrite; sulfuric acid / water / 1 h / 80 °C 1.2: 20 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 23 h / 20 °C 3.1: sodium carbonate; palladium diacetate / 1-methyl-pyrrolidin-2-one / 120 °C / Inert atmosphere; Sealed tube |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With palladium diacetate; sodium carbonate In 1-methyl-pyrrolidin-2-one at 120℃; Inert atmosphere; Sealed tube; | 1.g 2-Cyano-4-fluoro-6-methylbenzoic acid methyl ester (V) [T=methyl] A mixture of 2-bromo-4-fluoro-6-methyl-benzoic acid methyl ester (VI) (275 mg, 1.12 mmol), potassiumhexacyanoferrate (II) (206 mg, 0.56 mmol), anhydrous sodium carbonate (237 mg, 2.24 mmol) and palladium(II)acetate (5 mg, 0.0224 mmol) in 3 mL of N-methylpyrrolidone was heated at 120 0 in a sealed tube under argonatmosphere overnight. The reaction mixture was diluted with dichloromethane and filtered through a pad of Celite. The organic phase was washed with water (13 x 6 mL), brine (2 x 6 mL), dried over Na2SO4, filtered and concentrated. Column chromatography (n-hexane/ethyl acetate : 7/3) afforded 2-cyano-4-fluoro-6-methyl-benzoic acid methyl ester (76 mg, 35%).1H NMR (400.5 MHz, DMSO-d6) ppm 2.42 (s, 3H), 3.93 (s, 3H), 7.65 (dd, JHF = 9.6, JHH = 2.6 Hz, 1H), 7.85 (dd, JHF8.3, 2.6 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: Methyl pivalate; dibenzoyl peroxide; N-Bromosuccinimide / 3 h / 85 °C / Inert atmosphere 1.2: 3 h / 90 °C / Inert atmosphere 2.1: water; hydrogenchloride / 10 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: Methyl pivalate; dibenzoyl peroxide; N-Bromosuccinimide / 3 h / 85 °C / Inert atmosphere 1.2: 3 h / 90 °C / Inert atmosphere 2.1: sulfuric acid; acetic acid / 9.5 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Stage #1: 2-cyano-4-fluoro-6-methylbenzoic acid methyl ester With N-Bromosuccinimide; Methyl pivalate; dibenzoyl peroxide at 85℃; for 3h; Inert atmosphere; Stage #2: 4-(3-Aminopropyl)morpholine With triethylamine In acetonitrile at 90℃; for 3h; Inert atmosphere; | 1.h 6-fluoro-2-(3-morpholin-4-yl-propyl)-3-oxo-2,3-dihydro-1H-isoindole-4-carbonitrile (IV) [n=3; R1=morpholin-4-yl; X=null, as m=0 and R2=null] To a solution of 2-cyano-4-fluoro-6-methyl-benzoic acid methyl ester (V) (208 mg, 1.07 mmol) in methyl pivalate (2 mL), N-bromosuccinimide (310 mg, 1.74 mmol) and benzoylperoxide (20 mg, 0.097 mmol) were added. The reaction mixture was stirred at 85°C under nitrogen atmosphere for 3 h. Crude was filtered on Gooch and washed with toluene. Volatiles were evaporated and the residue was dissolved in acetonitrile (3 mL). Triethylamine (0.41 mL, 2.9 mmol) and 3-morpholin-4-yl-propylamine (XIII) (140 mg, 0.97 mmol) were added and the reaction mixture was stirredat 90°C for 3 h. Crude was diluted with dichloromethane and washed with 15% ammonium hydroxide. The organicphase was dried over Na2SO4, filtered and evaporated. Column chromatography (gradient from chloroform/methanol:96/4 to chloroform/methanol: 94/6) afforded 6-fluoro-2-(3-morpholin-4-yl-propyl)-3-oxo-2,3-dihydro-i H-isoindole-4-carbonitrile (IV) (130 mg, 40% yield).1H NMR (400.5 MHz, CDCl3) ppm 1.87 (quintet, J = 7.1 Hz, 2H), 2.34 - 2.49 (m, 6H), 3.62 - 3.74 (m, 6H), 4.45 (s,2H), 7.42 (dd, JH-F = 7.3 Hz, JH-H = 2.0 Hz, 1 H), 7.47 (dd, JH-F = 8.3 Hz, JH-H = 2.0 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Stage #1: 2-cyano-4-fluoro-6-methylbenzoic acid methyl ester With N-Bromosuccinimide; Methyl pivalate; dibenzoyl peroxide at 85℃; for 3h; Inert atmosphere; Stage #2: (1-cyclohexylpiperidin-4-yl)amine dihydrochloride With potassium carbonate In acetonitrile at 90℃; for 3h; Inert atmosphere; | 2.h 2-(1-Cyclohexyl-piperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carbonitrile (IV) [R F; n m 0; Ripiperidin-4-yl; R2 = 1-cyclohexyl] To a solution of 2-cyano-4-fluoro-6-methyl-benzoic acid methyl ester (V) (208 mg, 1.07 mmol) in methyl pivalate (2 mL), N-bromosuccinimide (310 mg, 1.74 mmol) and benzoylperoxide (20 mg, 0.097 mmol) were added. The reaction mixture was stirred at 85°C under nitrogen atmosphere for 3 h. Crude was filtered and washed with toluene. Volatiles were evaporated and the residue was dissolved in acetonitrile (3 mL). Potassium carbonate (670 mg, 4.85 mmol)and i-cyclohexyl-piperidin-4-ylamine dihydrochloride monohydrate (XIII) (265 mg, 0.97 mmol) were added and the reaction mixture was stirred at 90°C for 3 h. Crude was diluted with dichloromethane and washed with 15% ammonium hydroxide. The organic phase was dried over Na2SO4, filtered and evaporated. Column chromatography (dichloromethane/methanol/ammonia solution, 7N in methanol: 97/2/i) afforded 2-(i -cyclohexyl-piperidin-4-yl)-6- fi uoro-3-oxo-2,3-dihydro-i H-isoindole-4-carbonitrile (IV) (100 mg, 30%).1H NMR (400.5 MHz, DMSO-d6) 6 ppm 1.02-1.13 (m, iH), 1.16-1.27 (m, 4 H), 1.55- 1.62 (m, 1 H), 1.68-1.80(br. s., 7 H), 2.23 - 2.39 (m, 3 H), 2.87 - 2.97 (m, 2 H), 3.95 (br. s., 1 H), 4.52 (s, 2 H), 7.86 (dd, JHF = 8.3, JHH = 2.2Hz, 1 H), 7.98 (dd, JHF = 9.3, JHH = 2.2 Hz, 1 H).HRMS (ESI+): calcd. for C20H25FN30 [M + H] 342.1976; found 342.1988 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 0.25 h 1.2: 2 h / 20 °C 2.1: N,N-dimethyl-formamide / 5 h / 110 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In N,N-dimethyl-formamide; at 110℃; for 5h; | A solution of <strong>[877151-07-0]4-fluoro-2-iodo-6-methyl-benzoic acid methyl ester</strong> (VI) (26.02 g, 88.48 mmol) in 260 mL of N,Ndimethylformamide was treated with copper(I) cyanide (12.18 g; 0.136 mol) and stirred at 11000 for 5 h. The darkcolored mixture was allowed to cool to about 60C, treated with 105 g of Celite 560 coarse (Fluka) under efficient stirring and diluted with ethyl acetate (250 mL). After cooling to room temperature, the mixture was slowly poured in 0.25N aqueous sodium hydroxide (500 mL) and then filtered. The reaction flask and the panel were washed with ethyl acetate (100 mL). The aqueous layer was separated and extracted twice with ethyl acetate (250 mL + 100 mL). The combined organic extracts were washed with brine (200 mL), dried over Na2SO4 and concentrated underreduced pressure to give 22.00 g of raw product as yellow solid. This material was crystallized from n-hexane (40 mL): after cooling to room temperature the solid was collected by filtration and the mother liquors were concentrated under reduced pressure. The solid residue so obtained was crystallized from n-hexane (20 mL) yielding, after filtration of the solids, a second crop of product. The combined crops (14.15 g) were finally purified by chromatography eluting in gradient from n-hexane / methyl-tert-butylether 9:1 to n -hexane / ethyl acetate 9:1. Afterevaporation of the fractions 12.0 g (70%) of 2-cyano-4-fluoro-6-methyl-benzoic acid methyl ester (V) were obtained.1H NMR (400.5 MHz, DMSO-d6) ppm 2.42 (s, 3H), 3.93 (s, 3H), 7.65 (dd, JHF 9.6, JHH 2.6 Hz, 1H), 7.85 (dd, JHF8.3, 2.6 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 20 °C 2.1: hydrogenchloride / water / 2 °C 2.2: 5 °C / pH Ca. 7 2.3: 5 - 70 °C 3.1: sulfuric acid / water / 150 °C 4.1: sodium nitrite; sulfuric acid / water / 1 h / 80 °C 4.2: 20 °C 5.1: potassium carbonate / N,N-dimethyl-formamide / 23 h / 20 °C 6.1: sodium carbonate; palladium diacetate / 1-methyl-pyrrolidin-2-one / 120 °C / Inert atmosphere; Sealed tube |
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