Structure of 129946-63-0
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 129946-63-0 |
Formula : | C7H5F2N3 |
M.W : | 169.13 |
SMILES Code : | NNC1=CC(F)=C(C=C1F)C#N |
MDL No. : | MFCD04972812 |
InChI Key : | PCCAOKUPWXCHHG-UHFFFAOYSA-N |
Pubchem ID : | 10920925 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H319 |
Precautionary Statements: | P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 38.28 |
TPSA ? Topological Polar Surface Area: Calculated from |
61.84 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.14 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.08 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.77 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.59 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.16 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.35 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.87 |
Solubility | 2.27 mg/ml ; 0.0134 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.97 |
Solubility | 1.81 mg/ml ; 0.0107 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.73 |
Solubility | 0.316 mg/ml ; 0.00187 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 |
-6.56 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 |
1.0 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) |
1.94 |
* 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 |
---|---|---|
With sodium hydroxide; acetic acid; In methanol; water; | Example II-3 5 g (0.125 mol) of powdered sodium hydroxide are added to 13 g (0.076 mol) of <strong>[129946-63-0]4-cyano-2,5-difluorophenylhydrazine</strong> in 100 ml of methanol, the mixture is then heated at reflux temperature for 6 hours and subsequently evaporated in vacuo, the residue is transferred to 50 ml of water, the mixture is rendered neutral by the dropwise addition of acetic acid, and any solids which have precipitated are filtered off with suction and recrystallized from toluene. 9 g (65% of theory) of 4-cyano-2-fluoro-5-methoxyphenylhydrazine of melting point 155-156 C. are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium acetate; In water; acetic acid; | Example 3 At room temperature (about 20 C.), 7.9 g (0.047 mol) of <strong>[129946-63-0]2,5-difluoro-4-cyano-phenylhydrazine</strong> are added to 8.8 g (0.047 mol) of 4,4,4-trichloro-2-methyl-crotonaldehyde, 11.5 g (0.14 mol) of sodium acetate and 20 ml of water in 100 ml of acetic acid, and the mixture is stirred at 50 C. overnight. The mixture is allowed to cool to room temperature, stirred with water and filtered off with suction, and the residue is recrystallized from n-hexane. 7.2 g (62% of theory) of 2-(2,5-difluoro-4-cyano-phenyl)-5-methyl-pyridazin-3-one of melting point 223 C. are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; | STR116 12.05 g (0.1 mol) of pivaloyl chloride are added dropwise at 0 C. with stirring and ice-cooling to 16.9 g (0.1 mol) of <strong>[129946-63-0]4-cyano-2,5-difluorophenylhydrazine</strong> and 12.4 g (0.105 mol) of triethylamine in 50 ml of dichloromethane; when the addition is complete, the mixture is stirred at 20 C. for 10 hours and then evaporated in vacuo, the residue is distributed between dichloromethane and water, the organic phase is dried over sodium sulphate, and the solvent is removed in vacuo. 24.85 g (98% of theory) of 1-(4-cyano-2,5-difluorophenyl)-2-pivaloylhydrazine of melting point 167 C. are obtained. | |
With triethylamine; In dichloromethane; | Example VIII-1 12.05 g (0.1 mol) of pivaloyl chloride are added dropwise at 0 C. with stirring and ice-cooling to 16.9 g (0.1 mol) of <strong>[129946-63-0]4-cyano-2,5-difluorophenylhydrazine</strong> and 12.4 g (0.105 mol) of triethylamine in 50 ml of dichloromethane; when the addition is complete, the mixture is stirred at 20 C. for 10 hours and then evaporated in vacuo, the residue is distributed between dichloromethane and water, the organic phase is dried over sodium sulphate, and the solvent is removed in vacuo. 24.85 g (98% of theory) of 1-(4-cyano-2,5-difluorophenyl)-2-pivaloylhydrazine of melting point 167 C. are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; Petroleum ether; | STR58 1.1 g (0.125 mol) of <strong>[129946-63-0]4-cyano-2,5-difluorophenylhydrazine</strong> and 12.5 g (0.125 mol) of 2,4-pentanedione are stirred for 2 hours at room temperature in 250 ml of ethanol, and the mixture is subsequently heated at 70 C. for 15 hours and then evaporated in vacuo. The residue is stirred with petroleum ether and filtered off with suction. 28 g (96% of theory) of 4-(3,5-dimethyl-1-pyrazolyl)-2,5-difluorobenzonitrile of melting point 122 C. are obtained. | |
In ethanol; Petroleum ether; | Example 1 (Process a) 21.1 g (0.125 mol) of <strong>[129946-63-0]4-cyano-2,5-difluorophenylhydrazine</strong> and 12.5 g (0.125 mol) of 2,4-pentanedione are stirred for 2 hours at room temperature in 250 ml of ethanol, and the mixture is subsequently heated at 70 C. for 15 hours and then evaporated in vacuo. The residue is stirred with petroleum ether and filtered off with suction. 28 g (96% of theory) of 4-(3,5-dimethyl-1-pyrazolyl)-2,5-difluorobenzonitrile of melting point 122 C. are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ice-water; acetic acid; | STR59 5.2 ml (0.04 mol) of 2-acetylcyclohexanone (cf., for example, J. org. Chem. 34, 1425-1429 [1969]) are added to 6.76 g (0.04 mol) of <strong>[129946-63-0]4-cyano-2,5-difluorophenylhydrazine</strong> in 40 ml of glacial acetic acid, the reaction mixture is stirred at room temperature for 2 hours and then stirred into 250 ml of ice-water, the mixture is extracted with dichloromethane, dried over sodium sulphate and evaporated in vacuo, and the residue is recrystallized from dichloromethane/n-hexane. 3.21 g (23.5% of theory) of 4-(5-methyl-3,4-tetramethylene -1-pyrazolyl)-2,5-difluorobenzonitrile of melting point 120 C. are obtained. | |
In ice-water; acetic acid; | Example 2 (Process a) 5.2 ml (0.04 mol) of 2-acetylcyclohexanone (cf., for example, J. org. Chem. 34, 1425-1429 [1969]) are added to 6.76 g (0.04 mol) of <strong>[129946-63-0]4-cyano-2,5-difluorophenylhydrazine</strong> in 40 ml of glacial acetic acid, the reaction mixture is stirred at room temperature for 2 hours and then stirred into 250 ml of ice-water, the mixture is extracted with dichloromethane, dried over sodium sulphate and evaporated in vacuo, and the residue is recrystallized from dichloromethane/n-hexane. 3.21 g (23.5% of theory) of 4-(5-methyl-3,4-tetramethylene-1-pyrazolyl)-2,5-difluorobenzonitrile of melting point 120 C. are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 5,5-dimethyl-1,3-cyclohexadiene; | STR62 8.45 g (0.05 mol) of 4-cyano-2,5-difluorophenyl-hydrazine and 12.08 g (0.078 mol) of ethyl N-ethoxycarbonylethaneimidate (cf., for example, Chem. Ber. 119, 2444-2457 [1986]) are heated at reflux temperature for 8 hours in 50 ml of xylene, the mixture is then cooled to room temperature, and solids are filtered off with suction and recrystallized from dichloromethane/petroleum ether. 5.91 g (50% of theory) of 1-(4-cyano-2,5-difluorophenyl)3-methyl-4,5-dihydro-1,2,4-triazolin-5-one of melting point 174 C. are obtained |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With hydrazine; In 1,4-dioxane; for 16.0h; | 2,4,5-Trifluorobenzonitrile (1 g, 6.3 mmol) and hydrazine (610 mg, 19 mmol) were dissolved in dioxane (3 mL) and stirred for 16 h. The reaction mixture was partitioned between ethyl acetate (30 mL) and sat. NaHCO3 (20 mL). The organic layer was washed with brine (10 mL), dried (MgSO4), filtered and concentrated to give 4-hydrazino-2,5-difluorobenzonitrile (1.012 g, 93%) as a white solid. LC/MS: m/z (M+H)=170.0. 1H-NMR (400 MHz, DMSO-d6) delta (ppm): 4.41 (2H, br s), 6.93 (1H, dd), 7.51 (1H, dd), 8.22 (1H, br s). |
With hydrazine hydrate; In ethanol; water; | STR112 11 g (0.22 mol) of hydrazine hydrate are added to 30 g (0.19 mol) of 2,4,5-trifluorobenzonitrile (cf., for example, EP-A 191,181) in 120 ml of ethanol, the mixture is heated at reflux temperature for 2 hours, cooled to room temperature and concentrated in vacuo, the residue is stirred with 50 ml of water, and any product which has precipitated is filtered off with suction and dried. 24 g (75% of theory) of 4-cyano-2,5-difluorophenylhydrazine of melting point 158 C. are obtained. | |
With hydrazine hydrate; In ethanol; water; | Example II-1 11 g (0.22 mol) of hydrazine hydrate are added to 30 g (0.19 mol) of 2,4,5-trifluorobenzonitrile (cf., for example, EP-A 191,181) in 120 ml of ethanol, the mixture is heated at reflux temperature for 2 hours, cooled to room temperature and concentrated in vacuo, the residue is stirred with 50 ml of water, and any product which has precipitated is filtered off with suction and dried. 24 g (75% of theory) of 4-cyano-2,5-difluorophenylhydrazine of melting point 158 C. are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic acid; In methanol; ethyl acetate; | Reference Example 15 1,3-Thiazolin-2-one(2,5-difluoro-4-cyanophenyl) hydrazone (Compound No. 3-4) 2-Methylthio-2-thiazoline (1.0g, 7.52mmol), and <strong>[129946-63-0]2,5-difluoro-4-cyanophenylhydrazine</strong> (1.27g, 7.51mmol) were dissolved in methanol (20ml), and to the resulting mixture, trifluoroacetic acid (four drops) was added at room temperature, and then the resultant was stirred at 55 ØC for 48 hours. After cooling, the reaction mixture was evaporated, and the obtained residue was dissolved in ethyl acetate, washed with sodium bicarbonate solution and dried, and then the solvent was removed. The obtained residue was purified by silicagel column chromatography (chloroform:acetone=25:1) to give 1,3-thiazolin-2-one(2,5-difluoro-4-cyanophenyl) hydrazone(0.9g). 1H-NMR(CDCl3) delta:3.33(2H,t,J=6.6Hz), 3.70(2H, t, J=6.6Hz), 6.10(1H,br s), 6.60-6.78(1H,m), 7.09-7.17(1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | 2-(2-Cyclopropylacetyl)-5,5-dimethylcyclohexane-1,3-dione (351 mg, 1.58 mol) and <strong>[129946-63-0]4-hydrazino-2,5-difluorobenzonitrile</strong> (267 mg, 1.58 mmol) were combined with ACOH (0.4 mL) and EtOH (1.2 mL). The reaction was stirred at 25 C. for 2 hours. It was diluted with EtOAc (20 mL) and washed with sat. NaHCO3 (20 mL) and sat. NaCl (20 mL). The organic layer was dried over Na2SO4 and concentrated. Purification by gradient flash chromatography eluting with 0% to 50% EtOAc in hexanes provided 4-(3-cyclopropylmethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazol-1-yl)-2,5-difluorobenzonitrile (395 mg, 70%) as an orange solid (LC/MS m/z=356.0 [M+H]+). |
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