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Structure of 123-06-8
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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. : | 123-06-8 |
Formula : | C6H6N2O |
M.W : | 122.12 |
SMILES Code : | N#C/C(C#N)=C/OCC |
MDL No. : | MFCD00001854 |
InChI Key : | OEICGMPRFOJHKO-UHFFFAOYSA-N |
Pubchem ID : | 67152 |
GHS Pictogram: |
![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H301-H317-H334 |
Precautionary Statements: | P501-P261-P272-P270-P264-P280-P284-P302+P352-P342+P311-P362+P364-P304+P340-P333+P313-P301+P310+P330-P405 |
Class: | 6.1 |
UN#: | 3439 |
Packing Group: | Ⅲ |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.33 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 31.07 |
TPSA ? Topological Polar Surface Area: Calculated from |
56.81 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.48 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.49 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.95 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.62 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.34 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.53 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.77 |
Solubility | 20.6 mg/ml ; 0.168 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.25 |
Solubility | 6.83 mg/ml ; 0.0559 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.63 |
Solubility | 28.8 mg/ml ; 0.236 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 |
-6.7 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 |
2.0 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) |
2.26 |
* 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 |
---|---|---|
39% | With N-ethyl-N,N-diisopropylamine In ethanol at 20℃; for 3.5 h; | A solution of 2-Ethyl-2-thiopsuedourea hydrobromide (1.52 g, 8.19 mmol),(Ethoxymethylene)malononitrile (1.0 g, 8.19 mmol) and N,N-diisopropylethylamine (3.57 mL, 20.05 mmol) in ethanol (20 mL) was stirred at room temperature for 3.5 hours. The resultant solid was collected, washed with ethanol, and the dried under vacuum to provide the title compound as a light yellow solid (580 mg, 39percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With sodium methylate In ethanol; water | 4-Amino-5-cyano-2-ethylthiopyrimidine. A suspension of NaOMe (2.7 g, 50 mmol) in EtOH (200 mL) is added to a mixture of S-ethylisothiourea hydroiodide (11.58 g, 50 mmol), ethoxymethylidenemalononitrile (6.1 g, 50 mmol) and ethanol (250 mL) at 25° C. The reaction mixture is refluxed under N2 for 2 h, and then the solution is concentrated on a hot plate until precipitation is observed. After cooling, the solid is collected by suction filtration and is stirred in water at 25° C. Filtration and vacuum oven drying affords 4-amino-5-cyano-2-ethylthiopyrimidine (4.02 g, 45percent) as a brown solid. 1 H NMR δ (DMSO) 8.45 (1H, s), 7.90 (2H, brs), 3.00 (2H, q, J=7.3 Hz), 1.27 (3H, t, J=7.3 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In ethanol; for 2h;Reflux; | General procedure: A mixture of the appropriate phenylhydrazine (0.001 mol)and 10 mL of ethanol was stirred and allowed to reflux.Then, 2-(ethoxymethylene)malononitrile (0.001 mol) dissolvedin 10 mL of ethanol was slowly added. The reactionmixture was refluxed for 2 h. The reaction mixture waspoured into 50 mL of ice-cold water. The precipitate wascollected by filtration and washed with water to provide10a-c in 61-80% yield. |
80% | In ethanol; for 2h;Reflux; | General procedure: A mixture of the appropriate phenylhydrazine (0.001 mol) and10 mL of ethanol was stirred and allowed to reflux. Then, 2-(ethoxymethylene)malononitrile (0.001 mol) dissolved in 10 mL of ethanol was slowly added. The reaction mixture was refluxed for 2 h. The reaction mixture was poured into 50 mL of ice-cold water. The precipitate was collected by filtration and washed with water to produce 7-12 in 48-90% yield. |
In ethanol; for 3h;Reflux; | General procedure: A stirred mixture of para-substituted phenylhydrazine hydrochloride (0.025 mol) was dissolved inH2O (30 mL), then the pH of the mixture was adjusted to pH 7-8 by the dropwise addition of 10% NaOHsolution to form the free para-substituted phenyl hydrazines, which were then refluxed for 3 h withethoxymethylene malononitrile in an ethanol medium. After completion of the reaction, the reactionmixture was allowed to cool at room temperature, and the solid 2a-2d were filtered under vacuum. Thecrude products obtained were recrystallized from DMF to afford the pure products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; | EXAMPLE 1 A mixture containing 13.5 g. of 4-pyridinylmethyl methyl ketone, 12.2 g. of ethoxymethylenemalononitrile and 100 ml. of ethanol was refluxed with stirring for five hours and then allowed to cool to room temperature. The separated crystalline product was collected, washed with cold ethanol and dried in a vacuum oven at 60 C. to yield 14.2 g. of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, m.p. >300 C. The nuclear magnetic resonance and infrared spectra of this product were identical with the corresponding respective spectra of the same compound prepared by a different method, that is, by reacting 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone with alpha-cyanoacetamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of sodium ethoxide (1.15g, 50mmol), and acetamidine hydrochloride (4.7g, 50mmol) in ethanol solution (60mL) was stirred at room temperature for 1h. After this, the reaction mixture was filtered out affording filtrate. Then 2-(ethoxymethylene)malononitrile (6.1g, 50mmol) was added to the filtrate, and the mixture was stirred at room temperature for 3h. After this, the reaction mixture was filtered and washed with 10mL ethanol and dried to give the desired compound 4-amino-2-methylpyrimidine-5-carbonitrile 1a, which was used directly for the next step. Under the same condition, the intermediate compounds 1b and 1c were also prepared. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | In ethanol; for 2h;Reflux; | General procedure: A mixture of the appropriate phenylhydrazine (0.001 mol)and 10 mL of ethanol was stirred and allowed to reflux.Then, 2-(ethoxymethylene)malononitrile (0.001 mol) dissolvedin 10 mL of ethanol was slowly added. The reactionmixture was refluxed for 2 h. The reaction mixture waspoured into 50 mL of ice-cold water. The precipitate wascollected by filtration and washed with water to provide10a-c in 61-80% yield.5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carbonitrile (10a)Yield: 61%. MP: 173-174 C. IR (cm-1): 3297-3183; 2225;1662; 1568; 1222. 1H NMR (400 MHz, DMSO-d6, TMS, deltain p.p.m.): 7.31-7.25; (m; 2 H; H3?, H5?); 7.54-7.49; (m;2H; H2?, H6?); 7.67; (s; 1 H; H3). 13C NMR (100 MHz,DMSO-d6, TMS, delta in ppm): 73.2 (C4); 114.8 (CN); 116.3(d; J = 22.8 Hz; C3?, C5?); 126.9 (d; J = 8.9 Hz; C2?, C6?);133.7 (d; J = 2.8 Hz; C1?) 141.7 (C5); 151.4 (C3); 161.2 (d;J = 243.6 Hz; C4?). 19F NMR (376 MHz, DMSO-d6, TMS, deltain p.p.m.): -114.26. EI [M + 1]+ 203.07. |
61% | In ethanol; for 2h;Reflux; | General procedure: A mixture of the appropriate phenylhydrazine (0.001 mol) and10 mL of ethanol was stirred and allowed to reflux. Then, 2-(ethoxymethylene)malononitrile (0.001 mol) dissolved in 10 mL of ethanol was slowly added. The reaction mixture was refluxed for 2 h. The reaction mixture was poured into 50 mL of ice-cold water. The precipitate was collected by filtration and washed with water to produce 7-12 in 48-90% yield. |
In ethanol; for 3h;Reflux; | General procedure: A stirred mixture of para-substituted phenylhydrazine hydrochloride (0.025 mol) was dissolved inH2O (30 mL), then the pH of the mixture was adjusted to pH 7-8 by the dropwise addition of 10% NaOHsolution to form the free para-substituted phenyl hydrazines, which were then refluxed for 3 h withethoxymethylene malononitrile in an ethanol medium. After completion of the reaction, the reactionmixture was allowed to cool at room temperature, and the solid 2a-2d were filtered under vacuum. Thecrude products obtained were recrystallized from DMF to afford the pure products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.3% | With triethylamine; In ethanol; at 78.0℃; for 3.0h; | At room temperature, t-butylhydrazine 11 (0.72 g, 8.19 mmol) and triethylamine (1.70 mL, 12.29 mmol) were added to a 50 mL round bottom flask containing 20 mL of absolute ethanol.Then, ethoxymethylenemalononitrile 10 (1.00 g, 8.19 mmol) was slowly added dropwise thereto.The reaction mixture was heated at 78 C for 3 hours.The reaction solution was then cooled to room temperature and spin-dried to obtain a viscous orange solid.Water (30 mL) was then added thereto and the reaction was extracted with CH2Cl2 (3 x 60 mL). The combined organic phases were dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure and concentrated. A fast-curing orange-yellow gum was obtained. The residue was separated with 10% EtOAc in hexane (60 mL), and the mixture was sonicated. The resulting crystalline solid was filtered, washed with a large amount of 10% EtOAc in hexane, and dried to give 5-amino-4-cyano-1-t-butyl-1H-pyrazole 1.29 as a light orange crystal, with a yield of 96.3 %. |
83% | With triethylamine; In ethanol; at 100.0℃; for 0.5h;Microwave irradiation; | To a mixture of t-butylhydrazine (1.0 g, 8.2 mmol) and triethylamine (1.1 ml, 8.2 mmol) in anhydrous ethanol (20 ml) was added ethoxymethylene malononitrile (7, 1.0 g, 8.2 mmol) slowly in portions. The mixture was heated in a microwave at 100 C for 30 min. and then concentrated via evaporation of the solvent under a reduced pressure. The residue was washed with ether then dried under a reduced pressure. The product was isolated as a yellow solid in 83 % yield (1.1 g, 6.7 mmol). 1H NMR (200 MHz, CDCl3): delta 7.37 (s, 1 H), 4.54 (s, 2 H), 1.58 (s, 9 H); 13C NMR (50 MHz, CDCl3): delta 150.1, 138.3, 114.7, 77.8, 59.9, 28.9; HRMS (CI) calcd for C8H12N4 (M) 164.1062, found 164.1080. |
46 g (87%) | With sodium methylate; In ethanol; | (a) 1-tert-Butyl-5-amino-1H-pyrazole-4-carbonitrile To a mixture of tert-butylhydrazine (40 g, 0.32 mol), sodium methoxide (18 g, 0.32 mol) and ethanol 150 ml) was added ethoxymethylene malononitrile (42 g, 0.32 mol). The reaction mixture was heated to reflux for 2 hours and the solvent was removed in vacuo. The residue was extracted with chloroform, washed with water and the organic layer was concentrated in vacuo to afford 46 g (87%) of 1-tert-butyl-5-amino-1H-pyrazole-4-carbonitrile as a semi-solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine; In ethanol; water; at 78.0℃; for 3.0h; | Dissolve tert-butylhydrazine hydrochloride (8 g, 64.20 mmol) and triethylamine (6.50 g, 64.20 mmol) in 500 mL of absolute ethanol. Then, 2-ethoxymethylenemalononitrile (7.83 g, 64.20 mmol) was slowly added dropwise to the reaction flask with stirring. It was heated to reflux at 78 C. After about 3 h, the reaction was monitored by TLC (developer: PE / EtOAc = 1: 1). After the reaction solution was cooled to room temperature, the solvent was concentrated under reduced pressure to remove the solvent, and 100 mL of water and CH 2 Cl 2 (300 mL × 3) were added for extraction. The organic phases were combined, dried by adding an appropriate amount of anhydrous sodium sulfate, and concentrated to obtain an orange-yellow viscous solid. The obtained crude product was dissolved in 60 mL of an ethyl acetate-n-hexane (1: 9) mixed solution, sonicated for about 5 min, and allowed to stand. Observed that a large number of crystal forms precipitated, and filtered (washed 3 times with the ethyl acetate-n-hexane mixed solution). Drying gave 10.11 g of 1-tert-butyl-5-amino-1H-pyrazole-4-carbonitrile as an orange solid product, yield: 96%. |
96% | With triethylamine; In ethanol; at 78.0℃; for 3.0h; | tert-butylhydrazine hydrochloride (8g, 64.20mmol) and triethylamine (6.50g, 64.20mmol) In 500 mL of absolute ethanol, 2-ethoxymethylenemalononitrile (7.83 g, 64.20 mmol) was slowly added dropwise to the reaction flask with stirring.It was heated to reflux at 78 C. After about 3 h, the reaction was monitored by TLC (developer: PE / EtOAc = 1: 1).After the reaction solution was cooled to room temperature, the solvent was concentrated under reduced pressure to remove the solvent, and 100 mL of water and CH2Cl2(300 mL × 3) were added for extraction. The organic phases were combined, dried by adding an appropriate amount of anhydrous sodium sulfate, and concentrated to obtain an orange-yellow viscous solid.The obtained crude product was dissolved in 60 mL of an ethyl acetate-n-hexane (1: 9) mixed solution, sonicated for about 5 min, and allowed to stand. Observed that a large number of crystal forms precipitated, and filtered (washed 3 times with the ethyl acetate-n-hexane mixed solution) Drying gave 10.11 g of 1-tert-butyl-5-amino-1H-pyrazole-4-carbonitrile as an orange solid product, yield: 96%. |
94% | To a suspension of fe/ -butylhydrazine hydrochloride (15.0 g, 120.4 mmol) in ethanol (600 ml_) was added triethylamine (16.8 ml_, 120.4 mmol). The mixture was stirred for 60 min until the hydrazine had dissolved. Ethoxymethylenemalononitrile (14.7 g, 120.4 mmol) was added in portions and the reaction mixture was heated to 80 C and stirred at this temperature overnight. The reaction mixture was concentrated to dryness and the obtained residue was taken up in EtOAc. The organic layer was washed with water, dried over Na2S04, filtered and concentrated under reduced pressure. The solid was then recrystallized in DCM to afford 5-amino-1 -fe/?-butyl-pyrazole-4-carbonitrile (18.6 g, 1 13.4 mmol, 94% yield) as a light yellow solid. LC-MS (ES+, method 1): 1 .36 min, m/z 165.1 [M+H]+ |
83% | With triethylamine; In ethanol; for 3.0h;Reflux; | In tert-butylhydrazine hydrochloride (8.67 g, 69.6 mmol)Was added triethylamine (9.7 mL, 69.6 mmol)After adding anhydrous ethanol (460 mL), the mixture was stirred and dissolved at room temperature,Ethoxymethylenemalononitrile (8.5 g, 69.6 mmol) was added in small portions.After heating the solution to reflux for 3 hours,After cooling, the solvent was evaporated to give an orange solid.And extracted with ethyl acetate (0.5 L) and water (0.25 L)After drying by adding magnesium sulfate,The organic layer was evaporated to give an orange-yellow solid.The resulting solid was continuously washed with a 10% ethyl acetate in cyclohexane solution to give a crystalline solid5-amino-1-tert-butyl hydrogen - pyrazol-4-cyano 9.54g(Yield: 83%). |
83% | With triethylamine; In ethanol; at 20.0℃; for 3.0h;Reflux; | Triethylamine (9.7mL, 69.6mmol) was added to tert-butylhydrazine hydrochloride (8.67g, 69.6mmol) After adding absolute ethanol (460mL) and stirring at room temperature to dissolve, Ethoxymethylenemalononitrile (8.5 g, 69.6 mmol) was added in small portions, the solution was heated to reflux for 3 hours, and then the solvent was evaporated in vacuo to obtain a crude orange product. It was extracted with a mixed solution of ethyl acetate (0.5 L) and water (0.25 L), dried over anhydrous magnesium sulfate, and the organic layer was evaporated to obtain an orange solid. Continue to wash the obtained solid with a cyclohexane solution containing 10% ethyl acetate to obtain crystalline solid 5-amino-1-tert-butyl 1hydro-pyrazole-4-cyano 9.54g (yield 83% ). |
64.4% | With triethylamine; In ethanol; for 3.0h;Heating / reflux; | A mixture of t-butylhydrazine hydrochloride (4.67 g, 53 mmol) and triethylamine (5.35 g, 53 mmol) in anhydrous ethanol (250 ml) was stirred and ethoxymethylene malononitrile (6.47 g, 53 mmol) was slowly added in portions. The mixture was heated at reflux for 3 hr. The solvent was removed in vacuo and the product was crystallized from ethyl acetate -hexane followed by ether to afford the title compound as light pale brown crystals (5.6 g, 64.4 %); LC/MS, API-ES, Neg, (M-H)", 163.0. |
With triethylamine; In ethanol; for 3.0h;Heating / reflux; | A mixture of t-butylhydrazine hydrochloride (4.67 g, 53 mmol) and triethylamine (5.35 g, 53 mmol) in anhydrous ethanol (250 ml) was stirred and ethoxymethylene malononitrile (6.47 g, 53 mmol) was slowly added in portions. The mixture was heated at reflux for 3 hr. The solvent was removed in vacuo and the product was crystallized from ethyl acetate - hexane followed by ether to afford 5-amino-l-tert-butyl-lH-pyrazole-4-carbonitrile as light pale brown crystals (5.6 g, 34.1 mmol); LC/MS, API-ES, Neg, (M-H)", 163.0. | |
With triethylamine; In ethanol; at 82.0℃; for 3.0h;Inert atmosphere; | [0814] Example 1: 5-amino-1-(tert-butyl)-1H-pyrazole-4-carbonitrile (I1): . In a 250mL flame-dried argon purged round bottom flask, triethylamine (1.78g, 17.7mmol), and t- butyl hydrazine hydrochloride (1.56g, 12.5mmol) are dissolved in anhydrous ethanol (85mL). Ethoxymethylenemalononitrile (1.98g, 17.7mmol) is added slowly and reaction mixture is brought to reflux at 82C for 3 hours. The solvent is removed in vacuo and 10% ethyl acetate / hexane is added (5mL) and the mixture is sonicated (or simply utilize recrystallization from 10% ethyl acetate / hexane). The resulting crystalline solid is filtered, and washed with ether to yield I1. LC-MS (ES+) calcd for C8H12N4 (M+H)+ 165.11, found 165.05. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium ethanolate; In ethanol;Heating / reflux; | A mixture of <strong>[33906-30-8]2-hydrazinylbenzoic acid hydrochloride</strong> (10 g, 53 mmol), 2-(ethoxymethylene)malononitrile (6.5 g, 53.2mmol) and sodium ethoxide (4.85 g, 257 mmol) in EtOH (100 mL) was refluxed overnight then cooled to ambient temperature. Water was added and the mixture was stirred at ambient temperature for Ih then filtered. The solid was washed with H2O, EtOH and Et2O then dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In ethanol; at 20℃; for 12h; | Example 48 Step A: Ethoxylidenemalononitrile (3.2 g, 26.2 mmol) was added in portions over a period of 10 min. to a suspension of 2-hydrazinopyrimidine (2.87 g, 26 mmol) in absolute ethanol (13 mL). The mixture was stirred at rt overnight. The precipitated solid was filtered, washed with hexanes and dried in vacuo to obtain the title compound 48A (4.06 g, 84% yield). |
In ethanol; at 20℃; for 3h;Reflux; | (2) Synthesis of compound C: To a suspension of 15.0 g of Compound (B) separately obtained according to the procedure of Section (1) and 90 mL of ethanol was gradually added 17.5 g of ethoxymethylene malononitrile (manufactured by ALDRICH) at room temperature, and the internal temperature was elevated to 60C, followed by reflux for 3.0 hours. Then, the reaction liquid was cooled to room temperature and filtered. Subsequently, the reaction liquid was washed with 40 mL of ethanol, and the resulting crystals were dried at 60C for 3 hours to obtain 21.9 g of Compound (C). (1H-NMR(DMSO-d6), delta value TMS standard: 7.47 to 7.55(1H, t), 7.95 to 7.98(1H, s), 8.03 to 8.13(2H, brs), 8.85 to 8.92(2H, d)) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isopropyl alcohol; for 16h;Heating / reflux; | Example 4: Synthesis of 5,6-Difluoro-lH-benzo[d]imidazole EPO <DP n="31"/>EtOCH=C(CN)2 iPrOH [0088] A solution of 4,5-difluoro-2-nitroaniline (6)(1.0 g) in 30 niL of THF was treated with a solution comprised of 6 g OfNa2S2O4 and 3 g NaHCO3 in 30 niL of water. Methanol (10 mL) was added after the addition of the aqueous solution so that the mixture remained homogeneous. The mixture was stirred for two hours and then diluted with 100 mL of ethyl acetate and 100 mL of water. The organic layer was separated and the aqueous layer was extracted again with 100 mL of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to provide the crude intermediate 4,5-difluorobenzene-l,2-diamine (7). The intermediate was refluxed with (ethoxymethylene)malononitrile (1.1 g) in 25 mL of isopropyl alcohol for 16 h. The mixture was concentrated in vacuo and the resulting crude product was suspended in water and filtered. The precipitate was washed with water and air-dried to provide 380 mg of 5,6-difluoro-lH-benzo[d]imidazole (8). | |
In isopropyl alcohol; for 16h;Heating / reflux; | Example 4 Synthesis of 5,6-Difluoro-1H-benzo[d]imidazole A solution of 4,5-difluoro-2-nitroaniline (6)(1.0 g) in 30 mL of THF was treated with a solution comprised of 6 g of Na2S2O4 and 3 g NaHCO3 in 30 mL of water. Methanol (10 mL) was added after the addition of the aqueous solution so that the mixture remained homogeneous. The mixture was stirred for two hours and then diluted with 100 mL of ethyl acetate and 100 mL of water. The organic layer was separated and the aqueous layer was extracted again with 100 mL of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to provide the crude intermediate 4,5-difluorobenzene-1,2-diamine (7). The intermediate was refluxed with (ethoxymethylene)malononitrile (1.1 g) in 25 mL of isopropyl alcohol for 16 h. The mixture was concentrated in vacuo and the resulting crude product was suspended in water and filtered. The precipitate was washed with water and air-dried to provide 380 mg of 5,6-difluoro-1H-benzo[d]imidazole (8). | |
In isopropyl alcohol; for 16h;Heating / reflux; | A solution of 4,5-difluoro-2-nitroaniline (6)(1.0 g) in 30 mL of THF was treated with a solution comprised of 6 g OfNa2SaO4 and 3 g NaHCC>3 in 30 mL of water. Methanol (10 mL) was added after the addition of the aqueous solution so that the mixture remained homogeneous. The mixture was stirred for two hours and then diluted with 100 mL of <n="29"/>ethyl acetate and 100 mL of water. The organic layer was separated and the aqueous layer was extracted again with 100 mL of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to provide the crude intermediate 4,5-difluorobenzene-l,2-diamine (7). The intermediate was refluxed with (ethoxymethylene)malononitrile (1.1 g) in 25 mL of isopropyl alcohol for 16 h. The mixture was concentrated in vacuo and the resulting crude product was suspended in water and filtered. The precipitate was washed with water and air-dried to provide 380 mg of 5,6- difluoro-lH-benzo[d]imidazole (8). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium ethanolate; sodium hydride; In ethanol; at 20℃; for 2h;Heating / reflux; | Sodium hydride as a 60% dispersion in mineral oil (5.90 g, 1.2 eq, 0.147 mol.) was added slowly to ethanol (200 ml) at room temperature. To the solution of sodium ethoxide in ethanol was added 4-fluorophenylhydrazine hydrochloride (23.96 g, 1.2 eq, 0.147 mol.), addition of ethoxymethylene malonitrile (15.00 g, 1.0 eq, 0.123 mol.) shortly followed. The reaction mixture was heated to reflux with stirring for 2 hours. The reaction was then allowed to cool to room temperature, once at room temperature diethyl ether (50 ml) was added to the reaction mixture. The resultant precipitate was collected by filtration, washed with diethyl ether (2 x 100 ml) and dried in vacuo to give the title compound as a beige solid (21.5 g, 0.106 mol, 86%). LCMS: [M+H]+=203, Rt = 1.02 min, 100% purity. |
46% | With triethylamine; In ethanol; at 50℃; for 2h; | Example 5A8.7 g (53.5 mmol) of 4-fluorphenylhydrazine hydrochloride was suspended with 6.5 g (53.5 mmol) of ethoxymethylenemalononithle in 13 ml of ethanol, and 22.2 ml (160 mmol) of thethylamine were added. The reaction mixture was heated to 500C for 2 h. After cooling to room temperature the solvent was removed under reduced pressure. The remaining residue was treated with water (25 ml) and extracted three times with ethyl acetate. The organic layer was dried over sodium sulphate, filtered and the filtrate was concentrated under reduced pressure. The remaining residue was <n="60"/>purified by preparative MPLC (SiO2, eluent CH2CI2). 5.0 g (46% of theory) of the product were obtained as an oil, that solidifies over night.LC-MS (Method 1 ): RT = 1.06 minMS (ESI pos): m/z = 203 (M+H)+. |
General procedure: A stirred mixture of para-substituted phenylhydrazinehydrochloride (0.025 mol) was dissolved in H2O (30 mL), thenthe pH of the mixture was adjusted to pH 7-8 by the dropwiseaddition of 10% NaOH solution to form the free para-substitutedphenyl hydrazines, which were then refluxed for 3 h with ethoxymethylene malononitrile in an ethanol medium. After completionof the reaction, the reaction mixture was allowed to cool at room temperature, and the solid were filtered under vacuum. The crudeproducts obtained were recrystallized from anhydrous ethanol togive the light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; | EXAMPLE 3A 5-Amino-1-(4-methylphenyl)-1H-pyrazole-4-carbonitrile In analogy to the preparation of Example 1A, 2.16 g (57percent of theory) of the desired product are obtained starting from 3 g (18.9 mmol) of 4-methylphenylhydrazine hydrochloride, 2.3 g (18.9 mmol) of ethoxymethylenemalononitrile and 7.9 ml (56.7 mmol) of triethylamine. LC-MS (Method 1): Rt=3.0 min. MS (ESI pos): m/z=199 (M+H)+. | |
General procedure: A stirred mixture of para-substituted phenylhydrazinehydrochloride (0.025 mol) was dissolved in H2O (30 mL), thenthe pH of the mixture was adjusted to pH 7?8 by the dropwiseaddition of 10percent NaOH solution to form the free para-substitutedphenyl hydrazines, which were then refluxed for 3 h with ethoxymethylene malononitrile in an ethanol medium. After completionof the reaction, the reaction mixture was allowed to cool at room temperature, and the solid were filtered under vacuum. The crudeproducts obtained were recrystallized from anhydrous ethanol togive the light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; | EXAMPLE 15A 5-Amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carbonitrile In analogy to the preparation of Example 10A, 3.5 g (88% of theory) of the desired product are obtained starting from 4.1 g (18 mmol) of <strong>[6971-45-5]2-methoxyphenylhydrazine hydrochloride</strong>, 2.19 g (18 mmol) of ethoxymethylenemalononitrile and 10 ml (71.9 mmol) of triethylamine. m.p.: 129 C. MS (ESI pos): m/z=215 (M+H)+ 1H-NMR (300 MHz, DMSO-d6): delta=3.8 (s, 3H), 6.3 (s, 2H), 7.05 (t, 1H), 7.2 (d, 1H), 7.5 (t, 1H), 7.7 (s, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.7% | Acetimidamide hydrochloride (3.87 g, 40.9 mmol) was suspended in ethanol (10 mL). A solution of sodiumethoxide in ethanol (13.3 g, 40.9 mmol) was added and the mixture was stirred at room temperature for 30-40 minutes. The insoluble material was removed by filtration and washed with small volumes of ethanol. The filtrate was treated with 2-(ethoxymethylene)-malononitrile (2.50 g, 20.5 mmol). A thick precipitate rapidly dropped out of solution which stopped stirring. The mixture was diluted with additional ethanol (3-4 mL). Stirring resumed but was still inefficient. After one hour, the solid was collected by filtration, washed with small volumes of ethanol and dried with suction under house vacuum to give 4-amino-2-methylpyrimidine-5-carbonitrile. (Yield 2.05 g, 15.3 mmol, 74.7%). |
Tags: 123-06-8 synthesis path| 123-06-8 SDS| 123-06-8 COA| 123-06-8 purity| 123-06-8 application| 123-06-8 NMR| 123-06-8 COA| 123-06-8 structure
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