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CAS No. : | 123-06-8 | MDL No. : | MFCD00001854 |
Formula : | C6H6N2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OEICGMPRFOJHKO-UHFFFAOYSA-N |
M.W : | 122.12 | Pubchem ID : | 67152 |
Synonyms : |
|
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 : | 56.81 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.7 cm/s |
Log Po/w (iLOGP) : | 1.48 |
Log Po/w (XLOGP3) : | 0.49 |
Log Po/w (WLOGP) : | 0.95 |
Log Po/w (MLOGP) : | -0.62 |
Log Po/w (SILICOS-IT) : | 0.34 |
Consensus Log Po/w : | 0.53 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.77 |
Solubility : | 20.6 mg/ml ; 0.168 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.25 |
Solubility : | 6.83 mg/ml ; 0.0559 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.63 |
Solubility : | 28.8 mg/ml ; 0.236 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.26 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P501-P261-P272-P270-P264-P280-P284-P302+P352-P342+P311-P362+P364-P304+P340-P333+P313-P301+P310+P330-P405 | UN#: | 3439 |
Hazard Statements: | H301-H317-H334 | 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 |
---|---|---|
81% | With N-ethyl-N,N-diisopropylamine In ethanol at 20℃; | Ethoxymethylene)malononitrile (12.83 g, 105 mmol) and isopropylhydrazine hydrochloride (11.06 g, 100 mmol) were combined in EtOH (250 mL). Diisopropylethylamine (36.6 mL, 210 mmol) was added drop-wise, resulting in some warming of the reaction mixture. The reaction was allowed to stir for about 18 h at room temp. Volatiles were then removed in vacuo, and the resulting viscous yellow oil was dissolved in dichloromethane and loaded onto a short column of silica gel. The column was eluted with dichloromethane (about 300 mL), followed by a 1:1 mixture of EtOAc and hexanes (about 750 mL), and the EtOAc: hexanes eluant was concentrated under reduced pressure to provide C20 as a pale yellow solid. Yield: 12.1 g, 80.6 mmol, 81percent. LCMS m/z 151.1 (M+1). 1H NMR (400 MHz, DMSO-d5) δ 1.26 (d, J=6.6 Hz, 6H), 4.41 (septet, J=6.5 Hz, 1H), 6.52 (br s, 2H), 7.53 (s, 1H). |
65% | With sodium methylate In ethanol for 18 h; Reflux | Sodium methoxide (2.139 g, 39.60 mmol) was added to a solution of ethoxymethylenemalonitrile (2.198 g, 18.00 mmol) and isopropylhydrazine hydrochloride (2.212 g, 20.00 mmol) in Ethanol (50 mL, 800 mmol). The mixture was heated under reflux for 18 hours. The solvent was removed in vacuum, the residue partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over Na2SO4, concentrated in vacuum and purified on 25 g silica column, eluting with 25-30percent of ethyl acetate in heptane, to give 5-Amino-1-isopropyl-1H-pyrazole-4-carbonitrile (yield 1.77 g, 65percent). MS(ESI+): 151.2. 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J=6.4, 1H), 4.23 (ddd, J=19.8, 16.6, 9.8, 3H), 1.46 (d, J=6.6, 7H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With sodium ethanolate In ethanol at 5℃; for 8 h; | 1.22 g (10 mmol) of guanidine nitrate was dissolved in 50 ml of sodium ethoxide and ethanol, and 1.22 g (10 mmol) of ethoxymethylenemalonitrile was added at 5 ° C for 8 h. Appropriate amount of water was added and extracted with ethyl acetate The organic phase was washed with saturated brine and the organic phase was concentrated (the solvent was removed under reduced pressure). The residue was purified by silica gel column chromatography (eluent: dichloromethane = 1: 30, v / v) to give a white solid (compound of formula IV) in 71percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: for 0.166667 - 0.25 h; Reflux Stage #2: at 20℃; for 8 h; |
To the freshly prepared sodium ethoxide [sodium (0.83 g, 36 mmol) in 20 ml absolute ethanol] solution; guanidine hydrochloride (3.1 g, 32.8 mmol) was added and the reaction mixture was heated to reflux for 10-15 min, the clear solution immediately turned turbid white. The solution was filtered and washed with 10 mL absolute ethanol and the filtrate with combined washings was used further. To the filtrate, ethoxymethylene malononitrile (4 g, 32.8 mmol) was added in portions and the reaction mixture stirred for 8 h at room temperature, after which it was concentrated to dryness and the obtained residue was dissolved in glacial acetic acid at reflux temperature. On cooling yellow crystals started precipitating out. The product was filtered, washed with diethyl ether (2x20mL) and then dried to yield of 2, 4-diaminopyrimidine-5-carbonitrile (3.5 g, 79percent) as yellow solid. |
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 |
---|---|---|
95% | at 120℃; for 0.75 h; Sealed tube; Microwave irradiation | 3.2 5-Amino-4-cyano-1-phenyl-1H-pyrazole (3a) A solution of phenylhydrazine (2d) (0.45 mL, 4.2 mmol) and ethoxymethylenemalononitrile (1b) (0.51 g, 4.2 mmol) in EtOH (4 mL) was irradiated at 120 °C for 45 min in a sealed, pressure-rated Pyrex tube (10 mL) using a CEM Discover microwave synthesizer by moderating the initial power (100 W). After cooling in a flow of compressed air, the solvent was evaporated in vacuo. Purification by column chromatography on silica, eluting with light petroleum/EtOAc (5:1 v/v), gave the title compound (0.738 g, 95percent) as a light brown solid, mp 137-139 °C (lit. 29 mp 137 °C) (found: 185.0827. C10H9N4 [MH] requires 185.0822); FTIR (KBr)/cm-1 νmax 3302 (NH), 3240 (NH), 2230 (CN), 1577, 1530, 1368; 1H NMR (400 MHz; CDCl3) δ 7.58 (1H, s, H-3), 7.49-7.37 (5H, Ph), 4.52 (2H, br s, exch. D2O, NH2); 13C NMR (100 MHz, CDCl3) δ 141.9 (CH), 135 (C), 129.3 (C), 125.5 (CH), 124.1 (CH), 121.3 (CH), 115.6 (C), 86.2 (C); LRMS (APcI) m/z (rel intensity) 226 ([M+MeCNH]+, 100), 185 (MH+, 64). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | for 2 h; 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 61–80percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | for 2 h; 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 61–80percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With diethylamine In ethanolReflux; Enzymatic reaction | Step 1:To 5.0 g (32.65 mmo[) (4-nitropheny[)hydrazine and 9.10 mL (65.3 mmo[) N,Ndiethy[ethanamine in 90 mL ethano[ were added 3.987 g (32.65 mmo[) (ethoxymethy[ene)ma[ononitri[e. The reaction was stirred under ref[ux over night and coo[ed to rt. It was concentrated. The residue was disso[ved in dich[oromethane,washed with water and brine, dried over sodium su[fate and concentrated. The so[id was treated with hexane, fi[tered off and dried under vacuum affording 7.024 g (91percent) product which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With hydrazine In ethanol at 100℃; for 0.5 h; | Hydrazine (5 g, 0.156 mol) was carefully added into 2-(ethoxymethylene)malononitrile (8.64 g, 0.070 mol) in ethanol and heated on the steam-bath for 30 min. After completion of the reaction, white precipitate was gradually appeared that kept in a refrigerator overnight. The product was then filtered and washed with a small amount of cold ethanol to afford the desired product 5-amino-1H-pyrazole-4-carbonitrile (1) as white solid; (3.05 g, 86percent); mp 168-170 °C (Lit. mp 169-170 °C) [33]. |
81.7% | for 1 h; Reflux | Ethoxy methylene malonic eye 15.0g (0.12 µM) is slowly added at room temperature to 85percent hydrazine hydrate 12 ml (0.25 µM) in, the water bath heating reflux reaction 1h, in the reaction system by adding 10 ml of water. Placed in the refrigerator overnight, filtered, washing the filter cake, washing the yellow solid 10.6g, yield 81.7percent. The resulting spectrogram consistent with literature reports. |
45% | at 85℃; | Ν2Η42Ο (33 g, 640 mmol) was added to a solution of 2- (ethoxymethylene)malononitrile (20 g, 163.77 mmol) in acetic acid (200 mL) and the reaction was stirred overnight at 85°C. The resulting mixture was concentrated in vacuo and the residue was diluted with H20 (100 mL) and extracted with ethyl acetate (20 x 500 mL) and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to afford a residue which was purified by silica gel column chromatograpy with 50percent ethyl acetate in petroleum ether to afford 5-amino-lH-pyrazole-4-carbonitrile as a light yellow solid (8 g, 45percent). |
15 g | at 0 - 100℃; for 1 h; | To 2-(ethoxymethylene)propanedinitrile (20 g, 163.80 mmol) was added hydrazine hydrate (15.9 mL, 327.60 mmol) dropwise at 0 °C and the resultant reaction mixture was heated at 100 °C in a closed reagent bottle for 1 h. The reaction was monitored by TLC. After completion of reaction, the mixture was cooled to RT and water (50 mL) was added to the reaction mixture. The product was extracted using EtOAc (3x200 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 15 g of 5-amino-1H-pyrazole-4-carbonitrile as a light brown solid. |
15 g | at 0 - 100℃; for 1 h; Sealed tube | To 2-(ethoxymethylene)propanedinitrile (20 g, 163.80 mmol) was added hydrazine hydrate (15.9 mL, 327.60 mmol) dropwise at 0 °C and the resultant reaction mixture was heated at 100 °C in a closed reagent bottle for 1h. The reaction was monitored by TLC. After completion, the reaction mixture was cooled to RT and water (50 mL) was added. The product was extracted using EtOAc (3x200 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 15 g of 5- amino-1H-pyrazole-4-carbonitrile as a light brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | at 110 - 140℃; Reflux | A Vmixture of triethyl orthoformate (67.3 gm, 0.454 moles) and malononitrile (20.0 gm,0.302 moles) in acetic anhydride (77.2 gm, 0.75 moles) was refluxed for 4-5 hours at 110-140°C. The reaction was monitored by GC. V Reaction mixture was cooled to roomtemperature. Concentrated the reaction mixture at 70°C at reduced pressure to yield crude solid product, 2-(ethoxymethylene)malononitrile. The crude product was further purified either by vacuum distillation to yield pure product, 2-(ethoxymethylene)rnaiononitrile. |
98% | at 110 - 140℃; | Preparation of Example 1: 5-(5-(benzyisulfanyl)-1-methyi-1H-pyrazol-4-yl)-2-methyi-2H-tetrazoleStep 1: 2-(ethoxymethyiene)malononitrile• A mixture of triethyl orthoformate (67.3 gm, 0.454 moles) and malononitrile (20.0gm, 0.302 moles) in acetic anhydride (77.2 gm, 0.75 moles) was refluxed for 4-5 hours at110-140°C. The reaction was monitored by GC. Reaction mixture was cooled to roomtemperature. Concentrated the reaction mixture at 70°C at reduced pressure to yield crudesolid product, 2-(ethoxymethylene)malononitriie. The crude product was further purifiedeither by vacuum distillation to yield pure product, 2-(ethoxymethylene)malononitrile.Drywt : 36.0gmYield • : 1.80 w/w(98percent)HPLC purity : 99percent |
98% | at 110 - 140℃; | Step 1 : 2-(ethoxymethylene)malononitrile A mixture of triethyl orthoformate (67.3 gm, 0.454 moles) and malononitrile (20.0 gm, 0.302 moles) in acetic anhydride (77.2 gm, 0.75 moles) was refluxed for 4-5 hours at 1 10-140°C. The reaction was monitored by GC. Reaction mixture was cooled to room temperature. Concentrated the reaction mixture at 70°C at reduced pressure to yield crude solid product, 2- (ethoxymethylene)malononitrile. The crude product was further purified either by vacuum distillation to yield pure product, 2-(ethoxymethylene)malononitrile. Dry wt : 36.0 gm Yield : 1.80 w/w (98percent) HPLC purity : 99percent MP : 65-67 °C |
98% | at 110 - 140℃; | A mixture of triethyl orthoformate (67.3 gm, 0.454 moles) and malononitrile (20.0 gm, 0.302 moles) in acetic anhydride (77.2 gm, 0.75 moles) was refluxed for 4-5 hours at 110-140° C. The reaction was monitored by GC. Reaction mixture was cooled to room temperature. Concentrated the reaction mixture at 70° C. at reduced pressure to yield crude solid product, 2-(ethoxymethylene)malononitrile. The crude product was further purified either by vacuum distillation to yield pure product, 2-(ethoxymethylene)malononitrile. |
84.3% | for 6 h; Reflux | The c b eye 9.9g (0.15 µM), the original carboxylic acid triethyl ester 33.3g (0.23 µM) and acetic anhydride 38.4g (0.38 µM) added to the 250 ml flask in a single port. Reflux reaction 6h after, cooling, adding activated carbon to a postheating reflux 30min, heat filter, for washing the filter cake after the ethanol, the filtrate is placed into refrigerator over night, filtering, washing the yellow solid 15.4g, yield 84.3percent. The resulting spectrogram consistent with literature reports. |
65.2% | at 90℃; for 12 h; | General procedure for Preparation of Compound A:; A solution of mixture of triethyl orthoformate (11.2 g, 75 mmol) and malononitrile (5.0 g, 75 mmol) in acetic anhydride (15 rnL) was heated to 9O0C for 12h. After completion of reaction (TLC shows absent of S. M), the solvent (excess acetic anhydride and acetic acid) was removed under high vacuum. The residue (6.0 g, 65.2 percent of yield) was used in the next reaction without further purification.1H NMR (500 MHz, DMSO-d6) δ: 8.59 (s, IH), 4.55 (m, 2H), 1.38 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine In ethanol for 3.5 h; Heating / reflux | To 2-hydrazinopyridine (3.00 g, 27.5 [MMOL)] in 50 mL of ethanol was added 2- (ethoxymethylene) malononitrile (3.37 g, 27.5 [MMOL)] and triethylamine (3.8 [ML,] 27.5 [MMOL).] Mixture was [REFLUXED] of ca. 3.5 h. After cooling to RT the resulting solids were collected to give the product as a white solid (4.33 g, 85 percent). 'H NMR (DMSO) 8 8.46 [(DD,] [1] H), 8.11 (brs, 2H), 8.01 (m, 1 H), 7.88 (s, [1] H), 7.84 (d, [1] H), 7.35 (m, [1 H)] ppm. b |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium ethanolate; sodium hydride In ethanol at 20℃; for 2 h; Heating / reflux | Sodium hydride as a 60percent 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, 86percent). LCMS: [M+H]+=203, Rt = 1.02 min, 100percent purity. |
46% | With triethylamine In ethanol at 50℃; for 2 h; | 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 (46percent 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)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | for 2 h; 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 61–80percent yield.5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carbonitrile (10a)Yield: 61percent. MP: 173–174 °C. IR (cm−1): 3297–3183; 2225;1662; 1568; 1222. 1H NMR (400 MHz, DMSO-d6, TMS, δin 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, δ 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, δin p.p.m.): -114.26. EI [M + 1]+ 203.07. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With sodium ethanolate; sodium hydride In ethanol at 0℃; for 1 h; Heating / reflux | Sodium hydride as a 60percent dispersion in mineral oil (0.48 g, 1.2 eq, 12 mmol) was added slowly to ethanol (20 ml) at 0°C. To the solution of sodium ethoxide in ethanol was added 3-chlorophenylhydrazine hydrochloride (1.79 g, 1.0 eq, 10 mmol), addition of ethoxymethylene malonitrile (1.22 g, 1.0 eq, 10 mmol) shortly followed. The reaction mixture was heated to reflux with stirring for 1 hour. The reaction mixture was then allowed to cool to room temperature, once at room temperature a precipitate was observed. Ethanol (20 ml) was added to the slurry and the precipitate was collected by filtration, washed with diethyl ether (2 x 100 ml) and dried in vacuo to give the title compound as a yellow solid (1.56 g, 7.13 mmol, 72percent). LCMS: [M+H]+=219, Rt = 1.17 min, 100percent purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: With sodium ethanolate In ethanol at 0 - 20℃; Stage #2: at 20 - 80℃; for 2 h; Stage #3: With hydrogenchloride; water In ethanol |
Example 74 4-Amino-5-cyano-2-hydroxy-3-methylbenzoic acid ethyl ester (74) To a solution of sodium ethoxide (1.3 L) (freshly prepared by addition of sodium metal (7.9 g, 0.35 mol) to ethanol (1.3 L)) at 0° C. was added ethylpropionyl acetate (25 g, 0.17 mol) and the solution was stirred at RT for 1 h. To the above solution was added ethoxymethylene malonormitrile (21 g, 0.17 mol) at RT and the reaction mixture was refluxed at 80° C. for 2 h. The reaction mixture was cooled, neutralized to pH=7 by addition of 1.5 N HCl and concentrated under vacuum. The obtained residue was diluted with water (100 mL) and filtered. The solid was washed with water and dried under vacuum at 50° C. to give the crude product (27 g). The crude solid was washed with 5percent ethyl acetate in pet. ether which gave pure title compound (22.5 g, 59percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: at 20℃; for 12 h; Stage #2: at 20 - 80℃; for 2 h; |
Example 39: Alternative route for the preparation of compound 34Step A: Synthesis of 4-Amino-5-cyano-2-hydroxy-3-methylbenzoic acid ethyl ester (141)To a solution of sodium ethoxide (1.3 L) (freshly prepared by addition of sodium metal (7.9 g, 0.35 mol) to ethanol (1.3L)) at 0 °C was added ethylpropionyl acetate (25 g, 0.17 mol) and the solution was stirred at RT for Ih. To the above solution was added ethoxymethylene malononnitrile (21 g, 0.17 mol) at RT and the reaction mixture was refluxed at 80 °C for 2h. The reaction mixture was cooled, neutralized to pH=7 by addition of 1.5 N HCl and concentrated under vacuum. The obtained residue was diluted with water (100 mL) and filtered. The solid was washed with water and dried under vacuum at 50 °C to give the crude product (27 g). The crude solid was washed with 5percent ethyl acetate in pet. ether which gave pure title compound (22.5 g, 59percent). TLC: EIOAc/ Pet. ether, 3:7, Rf=QA |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | Stage #1: With sodium methylate In methanol at 20℃; for 0.25 - 0.333333 h; Stage #2: at 20℃; for 2.66667 h; Heating / reflux |
A round-bottomed flask (100 mL), equipped with a reflux condenser and N2 inlet septum, was charged with 4- (methylsulfonyl) phenylhydrazine hydrochloride (2 g, 9 mmol), and sodium methoxide (0. 49 g, 9 mmol). Methanol (20 mL) was added under a stream of nitrogen at room temperature. The reaction mixture was stirred for 15-20 minutes until the purple color disappeared and a white precipitate was formed. This was followed by the addition of ethoxymethylenemalononitrile (1.1 g, 9 mmol) and stirring at room temperature for an additional 10 mins, subsequently the reaction mixture was brought to reflux for 150 mins. The cooled reaction mixture was filtered and concentrated under reduced pressure to afford the crude product. The solid residue was dissolved in ETOAC/H20. The EtOAc layer was collected, washed with saturated aqueous NACI, dried OVER NAS04 AND concentrated to give second portion of the crude product. The crude product was purified by flash chromatography (10 percent CH3OH/CH2CI2) and recrystallized from methanol to give a yellow crystalline product (625 mg, 26 percent). 'H NMR (DMSO-D6, 400 MHz) No. 3. 27 (s, 3H), 6. 98 (s, 2H), 7. 81 (d, 2H), 7. 88 (s, 1H), 8. 06 (s, 2H). LCMS : calculated for CIIHIONAO2S 262. 05, observed 262. 9 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: With triethylamine In ethanol for 1 h; Stage #2: at 80℃; |
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, 94percent 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 h; 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 10percent ethyl acetate in cyclohexane solution to give a crystalline solid5-amino-1-tert-butyl hydrogen - pyrazol-4-cyano 9.54g(Yield: 83percent). |
64.4% | With triethylamine In ethanol for 3 h; 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 percent); LC/MS, API-ES, Neg, (M-H)", 163.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With triethylamine In ethanol at 100℃; for 0.5 h; 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 percent yield (1.1 g, 6.7 mmol). 1H NMR (200 MHz, CDCl3): δ 7.37 (s, 1 H), 4.54 (s, 2 H), 1.58 (s, 9 H); 13C NMR (50 MHz, CDCl3): δ 150.1, 138.3, 114.7, 77.8, 59.9, 28.9; HRMS (CI) calcd for C8H12N4 (M) 164.1062, found 164.1080. |
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 (87percent) of 1-tert-butyl-5-amino-1H-pyrazole-4-carbonitrile as a semi-solid. |
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