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USD 80+
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Structure of 1118-61-2 * Storage: {[proInfo.prStorage]}
* 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.
With hydrazine hydrate In ethanol at 85 - 95℃; Large scale
Add 10 g of 3-aminobutenenitrile and 5 L of ethanol to a 10 L reaction flask, stir to stir, stir until dissolved, and add 2500 g of 80percent hydrazine hydrate.Stir at room temperature for 10-20 min., slowly heat to reflux, the reaction temperature is 85-95 ° C;Note the large amount of gas generated;When the heat preservation reaction is 1.5-2.5, TLC monitoring, the raw material reaction is completed; the reaction liquid is concentrated under reduced pressure at 50-60 ° C to 20percent-30percent of the original reaction liquid volume;The oil pump is rectified to obtain a pale yellow liquid (light yellow solid after cooling), 2230 g, yield 94.2percent. The purity of 3-amino-5-methylpyrazole is above 98percent by GC and HPLC, and the single impurity is less than 0.5. percent.
75%
at 80℃; for 8 h;
S1. 2.46g 3-amino crotonitril (1) and 20mL mass fraction of 25percent hydrazine hydrate dissolved in 50mL three-necked flask;80 heated to reflux for 8h;After the reaction, excess hydrazine hydrate was drained under vacuum; the residue was distilled to give 3-amino-5-methylpyrazole (2) in 75percent yield;
Reference：
[1] Patent: CN108341782, 2018, A, . Location in patent: Paragraph 0018; 0019; 0021; 0022
[2] Patent: CN104844567, 2017, B, . Location in patent: Paragraph 0031; 0034; 0039; 0044
2
[ 1118-61-2 ]
[ 14678-02-5 ]
Yield
Reaction Conditions
Operation in experiment
80%
With hydroxylamine hydrochloride In water at 0 - 25℃;
186.9 g (2.69 moles) of hydroxylamine hydrochloride, 150 g (1.8 mol) 3-amino crotonitrile and 30 g (1 percent w/v) Fe3O4SiO2 was mixed in 3 L of water stirred for overnight in flask. After 12 h of reaction, the magnetic nanoparticles were removed using an external barium ferrite magnet. The reaction mixture was alkalized to pH 10 using 25 g of sodium carbonate. The mixture was filtered, the solids are stirred with 600 mL of ether and filtered. The obtained ether filtrate was combined with aqueous filtrate, ethereal layer was separated. The aqueous layer was extracted with ether (2 × 300 mL), the ether layer was dried over anhydrous MgSO4 (125 g), organic solvent stripped under vacuum to leave a solid which was dried over KOH under vacuum. The solid was recrystallized from water to give cream (pale pink) fine crystalline solid which was collected on porcelain, washed with cold water and dried. Melting point reported 83-85 °C, observed 82-84 °C. Yield 80 percent, 1 H NMR (CDCl3, 400 MHz): 2.25 (s, 3H, CH3), 4.9 (s, 2H, NH2), 5.0 (s, 1H, CH). 13C NMR (CDCl3, 400 MHz): 168.4, 164, 96.5 and 14.2, Mass 97.1 (M+1), Elemental anal: C4H6N2O (percent): C-48.97, H-6.16, N-28.56 and O-16.31. Found: C-48.4, H-5.98, N-28.2 and O-16.28.
Reference：
[1] Asian Journal of Chemistry, 2017, vol. 29, # 1, p. 124 - 128
[2] Journal of Heterocyclic Chemistry, 1973, vol. 10, p. 181 - 185
3
[ 1118-61-2 ]
[ 149-73-5 ]
[ 3435-28-7 ]
Yield
Reaction Conditions
Operation in experiment
26%
With ammonia In methanol at 130℃; for 15 h;
Example 5; Synthesis of 6-methyl-4-aminopyrimidine; In a pressure-resistant vessel made of stainless steel having an inner volume of 10 ml were charged 1.0 g (11.7 mmol) of 3-aminocrotonnitrile with purity of 96percent, 2.48 g (23.4 mmol) of methyl orthoformate and 1.42 g (17.5 mmol) of 21percent by weight ammonia-methanol solution, and the mixture was reacted under stirring at 130° C. for 15 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, 10 ml of isopropyl alcohol and 660 mg of activated carbon were added to the concentrate, and the mixture was stirred at 90° C. for 1 hour and then filtered. To the resulting filtrate was added 660 mg of activated carbon, and the mixture was again stirred at 90° C. for 1 hour. After filtration, the filtrate was concentrated, 1.8 ml of isopropyl alcohol and 3 ml of toluene were added to the concentrate, and the resulting mixture was heated up to 90° C., and gradually cooled and stirred at -5° C. for 1 hour. The precipitated solid was collected by filtration, and the solid was dried under reduced pressure to obtain 326 mg (Isolation yield; 26percent) of 6-methyl-4-aminopyrimidine with purity of 99.5percent (Areal percentage by gas chromatography) as white crystals. Physical properties of the 6-methyl-4-aminopyrimidine were as follows. 1H-NMR (DMSO-d6, δ (ppm)); 2.17 (3H, s), 6.25 (1H, s), 6.65 (2H, brs), 8.21 (1H, s) CI-MS (m/e); 110 (M+1)
Reference：
[1] Chemische Berichte, 1957, vol. 90, p. 2265,2270
10
[ 5444-80-4 ]
[ 1118-61-2 ]
[ 1721-23-9 ]
Reference：
[1] Archiv der Pharmazie (Weinheim, Germany), 1952, vol. 285, p. 80,84
[2] Chemische Berichte, 1939, vol. 72, p. 563,566
11
[ 1118-61-2 ]
[ 60-34-4 ]
[ 3524-32-1 ]
Yield
Reaction Conditions
Operation in experiment
60.4%
for 3 h; Reflux
To a solution of 3-aminocrotononitri.e (16.5 g, 0.2 mo.) in n-pentanoi (40 mL) was added methylhydrazine (12,9 g, 0.28 moi). The solution was maintained at reflux for 3 hours. The n-pentanol and the excess methylhydrazine were subsequently distilled off under reduced pressure, The beige precipitate obtained was taken up in heptanes (150 mL), filtered on a sinter funnel and then dried under vacuum at a temperature of 40 °C to afford the product 1 ,3-dimethyl-1 H-pyrazo.-5-amine as a beige solid (13.5 g, yield 60.4 percent).
Reference：
[1] Patent: WO2012/92880, 2012, A1, . Location in patent: Page/Page column 59
[2] Journal of the American Chemical Society, 1959, vol. 81, p. 2452,2455
[3] Patent: US6338741, 2002, B1, . Location in patent: Page column 15
[4] Journal of Combinatorial Chemistry, 2010, vol. 12, # 4, p. 510 - 517
12
[ 1118-61-2 ]
[ 43213-43-0 ]
[ 3524-32-1 ]
Reference：
[1] Chemistry of Heterocyclic Compounds, 2003, vol. 39, # 7, p. 937 - 942
13
[ 1118-61-2 ]
[ 50-01-1 ]
[ 1791-73-7 ]
Yield
Reaction Conditions
Operation in experiment
10.5 g
Stage #1: With sodium methylate In methanol at 20℃; for 0.5 h; Stage #2: at 110℃; for 10 h; Inert atmosphere
2,4-Diamino-6-methylpyrimidine was synthesized in accordance with the process described in Aust. J. Chem., 1984, vol. 37, pp. 1195-1201. (0362) Guanidine hydrochloride (23.8 g) was added to methanol (50 mL) and a solution of sodium methoxide in 28percent methanol (51 mL), followed by stirring at room temperature for 30 minutes. Subsequently, the precipitated salt was removed by filtration, followed by concentration under reduced pressure to give a guanidine-free product solution. Then, 3-amino crotononitrile (16.4 g) and 1-butanol (60 mL) were added to the solution. The reaction solution was stirred with heating at 110° C. for 10 hours under a nitrogen gas flow. After completion of the reaction, the precipitated salt was removed by hot filtration, and 100 mL of acetone was added to the remaining solution, followed by stirring under ice cooling for 30 minutes to give a crude product. The crude product was recrystallized from acetone to yield 10.5 g of 2,4-diamino-6-methylpyrimidine. (0363) Methyl benzoate (23 g: 169 mmol) and sodium methoxide (22 g: 407 mmol) were added to a solution of 2,4-diamino-6-methylpyrimidine (10 g: 81 mmol) in N-ethylpyrrolidone (100 mL), followed by stirring with heating at 40° C. for 2 hours. The temperature of the reaction system was decreased to room temperature. The reaction solution was poured into a 1N aqueous hydrochloric acid solution, and the solid component was collected by filtration. The crude product was recrystallized from 2-propanol to yield compound (1-2). (0364) The NMR spectrum of produced compound (1-2) is as follows. (0365) 1H-NMR (solvent: d6-DMSO, standard: tetramethylsilane) δ (ppm) 2.50 (3H, s) 7.45-7.70 (6H, m) 7.90 (1H, s) 7.95-8.05 (4H, m) 10.88 (1H, s) 11.10 (1H, s)
Reference：
[1] Australian Journal of Chemistry, 1984, vol. 37, # 6, p. 1195 - 1201
[2] Patent: US2016/159750, 2016, A1, . Location in patent: Paragraph 0361-0365
14
[ 1118-61-2 ]
[ 769-27-7 ]
Reference：
[1] Journal fuer Praktische Chemie (Leipzig), 1895, vol. <2> 52, p. 89[2] Journal fuer Praktische Chemie (Leipzig), 1908, vol. 78, p. 517[3] Chem. Zentralbl., 1908, vol. 79, # II, p. 593
[4] Journal fuer Praktische Chemie (Leipzig), 1895, vol. <2> 52, p. 89[5] Journal fuer Praktische Chemie (Leipzig), 1908, vol. 78, p. 517[6] Chem. Zentralbl., 1908, vol. 79, # II, p. 593
[7] Journal fuer Praktische Chemie (Leipzig), 1895, vol. <2> 52, p. 89[8] Journal fuer Praktische Chemie (Leipzig), 1908, vol. 78, p. 517[9] Chem. Zentralbl., 1908, vol. 79, # II, p. 593
[10] Journal fuer Praktische Chemie (Leipzig), 1895, vol. <2> 52, p. 89[11] Journal fuer Praktische Chemie (Leipzig), 1908, vol. 78, p. 517[12] Chem. Zentralbl., 1908, vol. 79, # II, p. 593
[13] Journal of the Chemical Society, 1902, vol. 81, p. 116
Reference：
[1] Journal fuer Praktische Chemie (Leipzig), 1908, vol. <2> 78, p. 512[2] Journal fuer Praktische Chemie (Leipzig), 1895, vol. <2> 52, p. 107[3] Chem. Zentralbl., 1908, vol. 79, # II, p. 593
[4] Journal fuer Praktische Chemie (Leipzig), 1889, vol. <2> 39, p. 239
17
[ 75-44-5 ]
[ 1118-61-2 ]
[ 769-27-7 ]
Reference：
[1] Journal fuer Praktische Chemie (Leipzig), 1908, vol. <2> 78, p. 512[2] Journal fuer Praktische Chemie (Leipzig), 1895, vol. <2> 52, p. 107[3] Chem. Zentralbl., 1908, vol. 79, # II, p. 593
[4] Journal fuer Praktische Chemie (Leipzig), 1895, vol. <2> 52, p. 89[5] Journal fuer Praktische Chemie (Leipzig), 1908, vol. 78, p. 517[6] Chem. Zentralbl., 1908, vol. 79, # II, p. 593
18
[ 1118-61-2 ]
[ 106-93-4 ]
[ 769-27-7 ]
Reference：
[1] Journal fuer Praktische Chemie (Leipzig), 1908, vol. <2> 78, p. 512[2] Journal fuer Praktische Chemie (Leipzig), 1895, vol. <2> 52, p. 107[3] Chem. Zentralbl., 1908, vol. 79, # II, p. 593
[4] Journal fuer Praktische Chemie (Leipzig), 1895, vol. <2> 52, p. 89[5] Journal fuer Praktische Chemie (Leipzig), 1908, vol. 78, p. 517[6] Chem. Zentralbl., 1908, vol. 79, # II, p. 593
19
[ 7647-01-0 ]
[ 64-17-5 ]
[ 1118-61-2 ]
[ 71-43-2 ]
[ 769-27-7 ]
Reference：
[1] Journal fuer Praktische Chemie (Leipzig), 1908, vol. <2> 78, p. 512[2] Journal fuer Praktische Chemie (Leipzig), 1895, vol. <2> 52, p. 107[3] Chem. Zentralbl., 1908, vol. 79, # II, p. 593
[4] Journal fuer Praktische Chemie (Leipzig), 1895, vol. <2> 52, p. 89[5] Journal fuer Praktische Chemie (Leipzig), 1908, vol. 78, p. 517[6] Chem. Zentralbl., 1908, vol. 79, # II, p. 593
20
[ 1118-61-2 ]
[ 100-63-0 ]
[ 1131-18-6 ]
Yield
Reaction Conditions
Operation in experiment
84%
Stage #1: With hydrogenchloride In water at 150℃; for 0.166667 h; Microwave irradiation; Sealed tube; Green chemistry Stage #2: With sodium hydroxide In water for 0.0833333 h; Sonication; Green chemistry
General procedure: In a 2-5mL microwave vial containing a stir bar, 3-aminocrotonitrile (164 mg, 2mmol) and 5 mL of 1M HCl were combined with stirring to give a 0.4 M solution of starting material. Next, phenylhydrazine (216 mg, 2 mmol) was added to the solution. The microwave vial was then sealed with an aluminum cap and irradiated in the microwave reactor at 150 °C for 10 m with the absorbance set to “very high.” After cooling, the orange sludge-containing heterogeneous solution was basified with 10percent NaOH and was sonicated for 5 m to produce a visible solid precipitate. The precipitate was filtered, washed twice with D.I. water, and then dried to yield the product as a light orange solid (292 mg, 84percent yield). For compounds that do not readily precipitate, the product can be isolated by extracting the basic aqueous layer 3x with dichloromethane (DCM). The combined organic layers are dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the product.
110 g
With hydrogenchloride In water at 110 - 115℃; for 4 h;
Step-1: To a stirred solution of 3-aminocrotononitrile (60 gm,) and 1N HCl (600 ml) was added phenyl hydrazine (72 ml). The reaction mass was strirred for 4 firs at 110-115° C. The reaction mixture was cooled to 25-30° C. and quenched in ice water (3.0 lit). This was then neutralised with sodium bicarbonate solution. The precipitated solid was then stirred, filtered and dried to get 110 gm of the title compound. (0201) 1H NMR (300 MHz, DMSO-D6) δ 2.05 (s, 3H), 5.25 (s, 2H), 5.30 (s, 1H), 7.25 (t, 1H, J=6.9 Hz), 7.43 (t, 2H, J=7.8 Hz), 7.56 (d, 2H, J=7.8 Hz); APCI-MS (m/z) 174.25 (M+H)+.
Reference：
[1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 42, p. 7806 - 7810
[2] Tetrahedron Letters, 2019, vol. 60, # 1, p. 72 - 74
[3] Chemistry of Heterocyclic Compounds, 2018, vol. 54, # 1, p. 51 - 57[4] Khim. Geterotsikl. Soedin., 2018, vol. 54, # 1, p. 51 - 57,7
[5] Journal of Organic Chemistry, 1993, vol. 58, # 22, p. 6155 - 6157
[6] Acta Chimica Academiae Scientiarum Hungaricae, 1980, vol. 105, p. 127 - 140
[7] Journal of Combinatorial Chemistry, 2010, vol. 12, # 4, p. 510 - 517
[8] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 19, p. 5891 - 5894
[9] Patent: WO2015/42085, 2015, A2, . Location in patent: Page/Page column 30
[10] Patent: WO2015/39333, 2015, A1, . Location in patent: Page/Page column 31
[11] Patent: WO2015/143653, 2015, A1, . Location in patent: Page/Page column 46
[12] ACS Combinatorial Science, 2016, vol. 18, # 5, p. 262 - 270
[13] Patent: US9518048, 2016, B2, . Location in patent: Page/Page column 25
[14] Journal of the Brazilian Chemical Society, 2018, vol. 29, # 1, p. 159 - 167
[15] Medicinal Chemistry Research, 2018, vol. 27, # 2, p. 388 - 405
[16] Mendeleev Communications, 2018, vol. 28, # 6, p. 584 - 586
Reference：
[1] Chemische Berichte, 1909, vol. 42, p. 67
26
[ 14798-97-1 ]
[ 1118-61-2 ]
Reference：
[1] Journal of Organometallic Chemistry, 1967, vol. 9, p. 125 - 134
27
[ 5765-44-6 ]
[ 7664-41-7 ]
[ 1118-61-2 ]
Reference：
[1] Chemische Berichte, 1909, vol. 42, p. 67
28
[ 60-29-7 ]
[ 816-43-3 ]
[ 75-05-8 ]
[ 1118-61-2 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1933, vol. 504, p. 94,126, 128
29
[ 60-29-7 ]
[ 925-90-6 ]
[ 75-05-8 ]
[ 1118-61-2 ]
Reference：
[1] Bulletin de la Classe des Sciences, Academie Royale de Belgique, 1922, vol. <5> 8, p. 18[2] Chem. Zentralbl., 1923, vol. 94, # I, p. 86
30
[ 1118-61-2 ]
[ 109-77-3 ]
[ 52603-48-2 ]
Reference：
[1] Liebigs Annalen der Chemie, 1990, # 12, p. 1215 - 1219
31
[ 1118-61-2 ]
[ 365-34-4 ]
[ 380238-10-8 ]
Yield
Reaction Conditions
Operation in experiment
73%
Stage #1: With hydrogenchloride In water for 12 h; Reflux Stage #2: With sodium hydroxide In water
General procedure: 3-aminocrotononitrile (48, 10 mmol) was added to a suspension of the appropriate arylhydrazine 49a-l (10 mmol) in 12M HCl-H2O (12 mL, 1:3), and the resulting mixture was heated under reflux for 12 hours and then cooled and neutralized with 2.5M sodium hydroxide solution. The suspension was extracted with CH2Cl2 (3x30 mL). The organic phases were washed with brine (20 mL), dried and the solvent evaporated in vacuo. The residue oil was triturated with hexane to obtain a solid which was separated by filtration. Subsequent chromatography was performed where indicated.
60%
Stage #1: With hydrogenchloride In water at 100℃; for 18 h; Stage #2: With sodium hydroxide In water
2.789 g (15.83 mmol) of 2-(trifluoromethyl)-phenylhydrazine was prepared in 15 ml of IN hydrochloric acid and 1.378 g (16.781 mmol) of 3-aminocrotonic nitrile was added. The mixture was stirred for 18 h at 1000C. After cooling, the pH value of the mixture was adjusted with IN sodium hydroxide solution to pH > 12. It was extracted with dichloromethane three times. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in a rotary evaporator at reduced pressure. The product was dried at high vacuum and purified by preparative HPLC (eluent: acetonitrile/water, gradient 20:80 -->90:10). We obtained 2.50O g (60percent of theor., purity 91percent according to HPLC) of the target compound.LC-MS (method 10): R, = 1.09 min; MS (EIpos): m/z = 242 [M+H]+.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 11, p. 3429 - 3445
[2] Patent: WO2010/20363, 2010, A1, . Location in patent: Page/Page column 136-137
[3] Journal of Combinatorial Chemistry, 2010, vol. 12, # 4, p. 510 - 517
Cyanoacetone (1) (E,Z)-3-Aminocrotonitrile (10 g, 0.12 mol) was dissolved in 6N HCl(28.5 mL), and the solution was stirred and heated to 80 C for 3 h.The reaction mixture was cooled, extracted several times with CH2Cl2,dried over anhydrous Na2SO4 and concentrated under vacuo.Yield: 5 g (53%); colourless liquid.171H NMR (400 MHz, CDCl3): delta = 3.56 (s, 2 H), 2.28 (s, 3 H).
With hydrogenchloride; water; at 20℃; for 1.25h;Product distribution / selectivity;
Example 1 (E)-2-[(dimethylamino)-methylene]-3-oxobutanenitrile A 2000 ml 3-neck Morton flask was equipped with an overhead stirrer, a N2 inlet, and a thermocouple. The flask was charged with water (500 g) and 36% hydrochloric acid (192.00 g, 12.18 mol). The resultant clear solution was stirred and cooled to room temperature, whereupon 3-aminocrotononitrile (100.19 g, 1.17 mol) was added portion-wise over about 15 minutes. The resultant solution was stirred at room temperature for about 1 h. The aqueous reaction mixture was then extracted twice with ethyl acetate (450.2 g portions). The organic extracts were then charged to a clean 2000 ml 3-neck Morton flask equipped with an overhead stirrer, an addition funnel, and a thermocouple. Stirring was initiated and dimethylformamide dimethyl acetal (165:11 g, 1.39 mol) was added dropwise via the addition funnel over about 18 minutes, while maintaining the internal temperature at <34 C. The resultant solution was stirred at room temperature for about 2 h. A solution of sodium bicarbonate (20.14 g, 0.24 mol) in water (200.0 g) was then added and the resultant biphasic mixture was stirred vigorously at room temperature for about 20 minutes. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated by rotary evaporation to yield an oil, which rapidly crystallized to yield the title compound as a low melting solid. 1H NMR (300 MHz, CDCl3): delta 7.82 (s, 1H), 3.41(s, 3H), 3.25(s, 3H), 2.35 (s, 3H) MS: (Cl): m/z 139 (M++1), 161 (M++Na) Elemental Analysis for C7H10N2O*0.17 H2O: Calculated: C, 59.53; H, 7.38; N, 19.84, H2O, 2.17. Found: C, 59.12; H, 7.62; N, 19.85, H2O, 2.04.
2,4-Diamino-6-methylpyrimidine was synthesized in accordance with the process described in Aust. J. Chem., 1984, vol. 37, pp. 1195-1201. (0362) Guanidine hydrochloride (23.8 g) was added to methanol (50 mL) and a solution of sodium methoxide in 28% methanol (51 mL), followed by stirring at room temperature for 30 minutes. Subsequently, the precipitated salt was removed by filtration, followed by concentration under reduced pressure to give a guanidine-free product solution. Then, 3-amino crotononitrile (16.4 g) and 1-butanol (60 mL) were added to the solution. The reaction solution was stirred with heating at 110 C. for 10 hours under a nitrogen gas flow. After completion of the reaction, the precipitated salt was removed by hot filtration, and 100 mL of acetone was added to the remaining solution, followed by stirring under ice cooling for 30 minutes to give a crude product. The crude product was recrystallized from acetone to yield 10.5 g of 2,4-diamino-6-methylpyrimidine. (0363) Methyl benzoate (23 g: 169 mmol) and sodium methoxide (22 g: 407 mmol) were added to a solution of 2,4-diamino-6-methylpyrimidine (10 g: 81 mmol) in N-ethylpyrrolidone (100 mL), followed by stirring with heating at 40 C. for 2 hours. The temperature of the reaction system was decreased to room temperature. The reaction solution was poured into a 1N aqueous hydrochloric acid solution, and the solid component was collected by filtration. The crude product was recrystallized from 2-propanol to yield compound (1-2). (0364) The NMR spectrum of produced compound (1-2) is as follows. (0365) 1H-NMR (solvent: d6-DMSO, standard: tetramethylsilane) delta (ppm) 2.50 (3H, s) 7.45-7.70 (6H, m) 7.90 (1H, s) 7.95-8.05 (4H, m) 10.88 (1H, s) 11.10 (1H, s)
5-Amino-3-methyl-1-(3,4-dichlorophenyl) pyrazole 3,4-Dichlorophenyl hydrazine HCl (50.0 g.) was reacted with 3-amino-2-butene nitrile (18.31 g.) as described in Example XLIII to give 18.7 g. product, mp 110-112. Analyzed for C10 H9 Cl2 N3; Theoretical; C=49.61, H=3.74, N=17.35 Found; C=50.09, H=3.75, N=17.43
To a solution of 16.4 g (0.2 mol) of 3-aminocrotononitrile in 100 cm3 of n-pentanol were added 19.4 g (0.22 mol) of tert-butylhydrazine. This solution was heated at reflux for 20 hours. The n-pentanol was subsequently distilled off under reduced pressure. A pale yellow solid was obtained, which was taken up in 100 cm3 of isopropyl ether at room temperature and filtered on a sinter funnel. After drying under vacuum at 40 C., 18 g of the expected product were obtained in the form of a pale yellow solid, the melting point of which was from 172 to 175 C.
With triethylamine; In ethanol;Reflux;
Step (i): Preparation of l-(tert-Butyl)-3-methyl-lH-pyrazol-5-amineTo a mixture of 3-aminobut-2-enenitrile (60 g, 731 mmol) and tert-butylhydrazine (96 g, 731.1 mmol) in ethanol (35 ml), triethylamine (220 ml, 2195 mmol) was added. The mixture was refluxed for 12-16 h. The reaction mixture was then concentrated under reduced pressure. The concentrate was extracted with water (100 ml) and ethylacetate (700 ml). The organic layer was washed with brine and dried over Na2SC>4 and concentrated under reduced pressure to obtain the title product..Η ΝΜΡν (400 MHz, CDC13) δ 5.37 (s, 1H), 3.51 (bs, 2H), 2.14 (s, 3H), 1.61 (s, 9H). MS (m/z): 154 (M++l, 100%).
2.000 g (11.453 mmol) of <strong>[6971-45-5]2-methoxyphenylhydrazine hydrochloride</strong> was put in 10 ml of IN hydrochloric acid and 0.997 g (12.140 mmol) of 3-aminocrotonic nitrile was added. The mixture was stirred for 18 h at 1000C. After cooling, the pH value of the mixture was adjusted with IN sodium hydroxide solution to pH > 12. It was extracted with dichloromethane three times. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in a rotary evaporator at reduced pressure. The product was dried under high vacuum. We obtained 2.430 g (purity according to LC-MS 91%, 95% of theor.) of the target compound.LC-MS (method 3): R, = 0.31 min; MS (EIpos): m/z = 204 [M+H]+.
86%
IM07: 2-(2-Methoxy-phenyl)-5-methyl-2H-pyrazol-3-ylamineTo a solution of (2-methoxy-phenyl)-hydrazine HCl salt (10.0 g, 57.3 mmol) in concentrated aqueous HCl (50 mL) was added 3-amino-but-2-enenitrile (5.0 g, 60.9 mmol) at room temperature. The reaction temperature was increased to 100 C. and the mixture was stirred at this temperature for 18 h. The reaction mixture was cooled to room temperature and then poured into ice-cold 2N NaOH solution (200 mL). The resulting mixture was filtered. The remanens was washed with water (200 mL) and dried in vacuo to give the title compound as an off-white solid (10.0 g, 86%). 1H NMR (DMSO-d6, 400 MHz) delta 7.39-7.35 (1H, m), 7.24-7.22 (1H, m), 7.17-7.15 (1H, m), 7.03-6.99 (1H, m), 5.21 (1H, s), 4.76 (2H, s), 3.78 (3H, s), 2.02 (3H, s).
86%
With hydrogenchloride; at 20 - 100℃; for 18h;
General procedure: To a solution of (2-methoxy-phenyl)-hydrazine HCI salt (10.0 g, 57.3 mmol) in concentrated aqueous HCI (50 mL) was added 3-amino-but-2-enenitrile (5.0 g, 60.9 mmol) at room tem- perature. The reaction temperature was increased to 100 C and the mixture was stirred at this temperature for 18 h. The reaction mixture was cooled to room temperature and then poured into ice-cold 2N NaOH solution (200 mL). The resulting mixture was filtered. The re- manens was washed with water (200 mL) and dried in vacuo to give the title compound as an off-white solid (10.0 g, 86 %). 1 H NMR (DMSO-d6, 400 MHz) delta 7.39-7.35 (1 H, m), 7.24-7.22 (1 H, m), 7.17-7.15 (1 H, m), 7.03-6.99 (1 H, m), 5.21 (1 H, s), 4.76 (2H, s), 3.78 (3H, s), 2.02 (3H, s).
General procedure: In a 2-5mL microwave vial containing a stir bar, 3-aminocrotonitrile (164 mg, 2mmol) and 5 mL of 1M HCl were combined with stirring to give a 0.4 M solution of starting material. Next, phenylhydrazine (216 mg, 2 mmol) was added to the solution. The microwave vial was then sealed with an aluminum cap and irradiated in the microwave reactor at 150 C for 10 m with the absorbance set to ?very high.? After cooling, the orange sludge-containing heterogeneous solution was basified with 10% NaOH and was sonicated for 5 m to produce a visible solid precipitate. The precipitate was filtered, washed twice with D.I. water, and then dried to yield the product as a light orange solid (292 mg, 84% yield). For compounds that do not readily precipitate, the product can be isolated by extracting the basic aqueous layer 3x with dichloromethane (DCM). The combined organic layers are dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the product.
87%
3-Aminocrotonitrile (2.00 g, 24.4 MMOL) was added to a stirred solution of (2- methylphenyl) hydrazine hydrochloride (3.67 g, 23.1 MMOL) in 1 M hydrochloric acid (20 mL). The reaction was heated (100C) for 18 h and then cooled to rt. The solution was adjusted to pH > 12 using 1 M aqueous sodium hydroxide. The mixture was extracted with dichloromethane (3 x 20 mL), and then the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 25-50% ethyl acetate/hexane afforded 3-METHYL-1-(2-METHYLPHENYL)-1H-PYRAZOL-5-AMINE (3.97 g, 87%) as an orange oil. H NMR (300 MHz, acetone-d6) 6 7.29 (m, 4 H), 5.32 (s, 1 H), 2.12 (s, 3 H), 2.08 (s, 3 H); ES-MS m/z 188.2 (MH+), HPLC RT (min) 0.79.
Example 5; Synthesis of 6-methyl-4-aminopyrimidine; In a pressure-resistant vessel made of stainless steel having an inner volume of 10 ml were charged 1.0 g (11.7 mmol) of 3-aminocrotonnitrile with purity of 96%, 2.48 g (23.4 mmol) of methyl orthoformate and 1.42 g (17.5 mmol) of 21% by weight ammonia-methanol solution, and the mixture was reacted under stirring at 130 C. for 15 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, 10 ml of isopropyl alcohol and 660 mg of activated carbon were added to the concentrate, and the mixture was stirred at 90 C. for 1 hour and then filtered. To the resulting filtrate was added 660 mg of activated carbon, and the mixture was again stirred at 90 C. for 1 hour. After filtration, the filtrate was concentrated, 1.8 ml of isopropyl alcohol and 3 ml of toluene were added to the concentrate, and the resulting mixture was heated up to 90 C., and gradually cooled and stirred at -5 C. for 1 hour. The precipitated solid was collected by filtration, and the solid was dried under reduced pressure to obtain 326 mg (Isolation yield; 26%) of 6-methyl-4-aminopyrimidine with purity of 99.5% (Areal percentage by gas chromatography) as white crystals. Physical properties of the 6-methyl-4-aminopyrimidine were as follows. 1H-NMR (DMSO-d6, delta (ppm)); 2.17 (3H, s), 6.25 (1H, s), 6.65 (2H, brs), 8.21 (1H, s) CI-MS (m/e); 110 (M+1)
Ethyl 2- { [2-D, 3-DIOXOISOINDOLIN-2-YDETHOXY] METHYL}-4- (2-CHLOROPHENYL)-5-CYANO-6- methyl-1,4-dihydropyridine-3-carboxylate. A mixture of 2-chlorobenzaldehyde (2.64 g; 18.79 mmol), 3-aminocrotononitrile (1.54 g; 18.79 MMOL), and ethyl 4- [2- (1, 3- dioxoisoindolin-2-yl) ethoxy] -3-oxobutanoate (6 g; 18. 79 mmol) in MeOH is heated to reflux for 6 days. After cooling, the solvent is removed under reduced pressure and the crude product is purified on a silica gel column to obtain the product in 70% yield as a light yellow solid.
4-(3-ethoxy-4-hydroxy-5-nitro-phenyl)-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; for 17.0h;Heating / reflux;
(b). 4-(3-Ethoxy-4-hvdroxy-5-nitro-phenviy2-methyl-5-oxo-7-propyl-l,4,5, 6,7,8- hexahydro-quinoline-3 -carbonitrileA mixture of <strong>[178686-24-3]3-ethoxy-4-hydroxy-5-nitro-benzaldehyde</strong> (1.5 g), 3-aminocrotonitrile (584 mg) and 5-propylcyclohexane-l,3-dione (1.09 g) in ethanol (60 ml) was heated at reflux for 17 h. The mixture was concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0 - > 0/1 (v/v) as eluent. EPO <DP n="43"/>Yield: 1.3 g. MS-ESI: [M+H]+ = 412.3
General procedure: In a 2-5mL microwave vial containing a stir bar, 3-aminocrotonitrile (164 mg, 2mmol) and 5 mL of 1M HCl were combined with stirring to give a 0.4 M solution of starting material. Next, phenylhydrazine (216 mg, 2 mmol) was added to the solution. The microwave vial was then sealed with an aluminum cap and irradiated in the microwave reactor at 150 C for 10 m with the absorbance set to “very high.” After cooling, the orange sludge-containing heterogeneous solution was basified with 10% NaOH and was sonicated for 5 m to produce a visible solid precipitate. The precipitate was filtered, washed twice with D.I. water, and then dried to yield the product as a light orange solid (292 mg, 84% yield). For compounds that do not readily precipitate, the product can be isolated by extracting the basic aqueous layer 3x with dichloromethane (DCM). The combined organic layers are dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the product.
With hydrogenchloride; In water;
5-Amino-1-(4-fluorophenyl)-3-methyl-pyrazole 4-Fluorophenylhydrazine HCl (60.0 g.) 175 ml. water, 70 ml. concentrated hydrochloric acid and 28.8 g. 3-amino-2-butene nitrile were refluxed one hour. The solution was cooled and made basic with concentrated ammonia. The solid was filtered and crystallized from ether to get 51.05 g. product, mp 108-110, which was converted to the HCl salt mp 227-229 Analyzed for C10 H10 FN3.HCl: Theoretical; C=52.76, H=4.87, N=18.47 Found; C=52.96, H=4.87, N=18.36
With hydrogenchloride; In water;
5-Amino-1-(4-fluorophenyl)-3-methyl-pyrazole 4-Fluorophenylhydrazine HCl (60.0 g.) 175 ml. water, 70 ml. concentrated hydrochloric acid and 28.8 g. 3-amino-2-butene nitrile were refluxed one hour. The solution was cooled and made basic with concentrated ammonia. The solid was filtered and crystallized from ether to get 51.05 g. product, mp 108-110, which was converted to the HCl salt mp 227-229 Analyzed for C10 H10 FN3 ·HCl: Theoretical; C=52.76, H=4.87, N=18.47. Found; C=52.96, H=4.87, N=18.36.
5-Amino-3-methyl-1-(4-chloro-2-methylphenyl) pyrazole <strong>[5446-17-3]5-chloro-2-methylphenylhydrazine HCl</strong> (80.32 g.) was reacted with 3-amino-2-butene nitrile (32.5 g.) as described in Example XLIII to give 60.5 g. product, mp 86-87. Analyzed for C11 H12 ClN3: Theoretical; C=59.59, H=5.45, N=18.95 Found; C=59.44, H=5.49, N=18.73.
5-Amino-3-methyl-1-(4-chloro-2-methylphenyl) pyrazole <strong>[5446-17-3]5-chloro-2-methylphenylhydrazine HCl</strong> (80.32 g.) was reacted with 3-amino-2-butene nitrile (32.5 g.) as described in Example XLIII to give 60.5 g. product, mp 86-87. Analyzed for C11 H12 ClN3: Theoretical; C=59.59, H=5.45, N=18.95. Found; C=59.44, H=5.49, N=18.73.
Example 1Furan-2-carboxylic acid {4-r2-bromo-4-(3-cvano-2-methyl-5-oxo-7-propyl-l,4,5, 6,7,8- hexahvdro-quinolin-4-yl)-6-ethoxy-phenoxyl-but-2-enyl}-amide(a). 4-(3-Bromo-5-ethoxy-4-hvdroxy-phenyl)-2-methyl-5-oxo-7-propyl-l,4,5, 6,7,8- hexahydro-quinoline-3 -carbonitrile;A mixture of <strong>[3111-37-3]3-bromo-5-ethoxy-4-hydroxy-benzaldehyde</strong> (6 g), 3-aminocrotonitrile (2.01 g) and S-propylcyclohexane-l^-dione (3.8 g) in ethanol (20 ml) was stirred at 8O0C for 4 h. The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel in heptane/EtOAc = 1/1 (v/v) as eluent. Yield: 6.3 g. MS-ESI: [M+H]+ = 445/447
To asolution of <strong>[78583-82-1]5-amino-3-(4-bromophenyl)pyrazole</strong> (50.4 mmol) in acetic acid (190ml) was added 3-aminocrotonitrile (50.4 mmol). The reaction mixture was heatedat 110C for 4h, then the solvent were evaporated under reduced pressure. Theresidue was triturated with saturated aqueous NaHCO3 solution. Theprecipitate was filtered and washed with water to give intermediate 4 in 98% yield: : 1H NMR (DMSO-d6,400 MHz) d(ppm) 2.33 (s, 3H), 5.96 (s, 1H), 6.73 (s, 1H), 7.56 (m, 2H), 7.65 (d, 2H), 7.97(d, 2H).
5-Amino-3-(4-bromophenyl)pyrazole (5 g) was dissolved in acetic acid (80 ml.) and 3- aminocrotonitrile (1.7 g) was added. The reaction mixture was stirred at 11O0C for 3 h and was then allowed to cool to room temperature. The solvent was evaporated in vacuo and the residue taken up in saturated sodium bicarbonate solution. The solid was then filtered <n="43"/>off, washed with water and isopropanol and dried in a vacuum oven at 4O0C to give the title compound.MS calcd for (C13H11N4Br+ H) + : 303/305MS found (electrospray): (M+H)+= 303/305
A mixture of 1 H-<strong>[253801-04-6]indazole-5-carboxaldehyde</strong> from Synthetic Preparation 1 (447 mg, 3.1 mmol) and 3-aminocrotononitrile (526.4 mg, 6.41 mmol) in HOAc (10 mL) was kept at 1 10 0C for 1.5 hr, after which it was cooled to rt. The reaction was treated with NaHCO3 (sat.) to pH 10, and extracted with EtOAc. The organic phases were combined, washed with brine, and dried. Concentration followed by purification with flash chromatography afforded 1 ,4-dihydro-4-(1 H-indazol-5-yl)-2,6-dimethyl-3,5-pyridinedicarbonitrile (370 mg, 44%) (Cpd. No. 80, Table 2). 1 H-NMR (400 MHz, CDCI3): delta = 8.07 (s, 1 H), 7.64 (s, 1 H), 7.53 (d, 1 H)1 7.35 (d, 1 H), 4.48 (s, 1 H), 2.03 (s, 6H) ppm.
1,4-dihydro-2-(4-chloropyrid-3-yl)-6-methyl-4-(1H-indazol-5-yl)-3,5-pyridinedicarbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39.3%
SYNTHETIC EXAMPLE 6A mixture of theta-chloro^'-oxo-S-pyridinepropanenitrile (1.2 g, 6.64 mmol), from Synthetic Preparation 4, and 1 H-<strong>[253801-04-6]indazole-5-carboxaldehyde</strong> (0.81 g, 5.54 mmol) was kept at reflux in EtOH (50 ml.) for 15 min, and 3-aminocrotononitrile (475 mg, 5.79 mmol) was added. The reaction mixture was kept at reflux for 2 hr, then HOAc was added. The reaction mixture was heated to reflux for 1.5 hr, and cooled to rt. All solvents were removed under vacuum, and the crude product was purified by column to afford 1 ,4-dihydro-2-(4- chloropyrid-3-yl)-6-methyl-4-(1 H-indazol-5-yl)-3F5-pyridinedicarbonitrile (974 mg, 39.3%) (Cpd. No. 270, Table 5). 1 H-NMR (400 MHz1 DMSO-D6): delta = 13.10 (s, 1 H)1 9.70 (s, 1H)1 8.32 (S, 1H), 8.10 (S1 1H)1 7.75 (m, 2H), 7.60 (m, 1H), 7.39 (m ,1H)1 6.95 (m, 1H), 4.64 (s, 1 H), 3.70 (m, 4H), 3.55 (m, 4H), 2.13 (s, 3H) ppm.
<strong>[218301-22-5]2-Fluoro-5-formylbenzonitrile</strong> (30 g, 201.17 mmol) and 3-aminocrotononitrile (35.01 g, 431.63 mmol) were dissolved in acetic acid and heated to 9O0C. After 4hr, the reaction mixture was cooled to rt, concentrated, neutralized with a saturated solution of sodium bicarbonate, and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated. The solid were dissolved into ethyl acetate, and hexane was added. The solid precipitated, and was filtered to afford 4-(3-cyano-4-fluorophenyl)-1 ,4- dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrile (44.9 g, 80.2%) as a pale yellow solid. 1 H- NMR (400 MHZ, DMSO-D6): delta = 9.61 (br. s, 1 H), 7.97 (dd, 1 H), 7.48 (dd, 1 H), 7.35 (dd, 1 H), 4.64 (s, 1 H), 2.01 (s, 6H) ppm.
80%
Example IA4-(3-Cyano-4-fluorophenyl)-2,6-dimethyl-l,4-dihydropyridine-3,5-dicarbonitrile 3O g (201.2 mmol) <strong>[218301-22-5]2-fluoro-5-formylbenzonitrile</strong> and 35 g (431.6 mmol) 3-aminocrotononitrile were dissolved in acetic acid (500 ml) and heated to 90C. After 4 h, the reaction mixture was cooled to rt, concentrated, neutralized with a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The organic extracts were combined, dried over sodium sulfate and concentrated under reduced pressure. The remaining solid was dissolved in ethyl acetate, and hexane was added. The precipitate was filtered off to afford the title compound (45 g, 80% of th.) as a pale yellow solid.1H-NMR (400 MHz, DMSO-Cl6): ? = 9.61 (br. s, IH), 7.97 (dd, IH), 7.48 (dd, IH), 7.35 (dd, IH), 4.64 (s, IH), 2.01 (s, 6H) ppm.
5.040 g (27.911 mmol) <strong>[40594-29-4]2,4-difluorophenylhydrazine hydrochloride</strong> was suspended in 28 ml of IN hydrochloric acid and 2.429 g (29.586 mmol) of 3-aminocrotonic nitrile was added. The mixture was stirred for 18 h at 1000C. After cooling, the pH value of the mixture was adjusted with IN sodium hydroxide solution to pH > 12. It was extracted with dichloromethane three times. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in a rotary evaporator at reduced pressure. The residue was purified by silica-gel chromatography (eluent: iso-hexane/ethyl acetate, gradient 85:15 - > 10:90).We obtained 4.740 g (81% of theor.) of the target compound.LC-MS (method 4): R, = 0.52 min; MS (EIpos): m/z = 210 [M+H]+.IH-NMR (400 MHz, DMSO-D6): delta [ppm] = 2.03 (s, 3H), 5.14 (sbr, 2H), 5.22 (s, IH), 7.15-7.21 (m, IH), 7.14-7.50 (m, 2H).
?.00 g (23.167 mmol) of <strong>[56737-78-1]2,5-dimethylphenylhydrazine hydrochloride</strong> was suspended in 23 ml of IN hydrochloric acid and 2.016 g (24.557 mmol) of 3-aminocrotonic nitrile was added. The mixture was stirred for 18 h at 1000C. After cooling, the pH value of the mixture was adjusted with IN sodium hydroxide solution to pH > 12. It was extracted with dichloromethane three times. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in a rotary evaporator at reduced pressure. We obtained 4.301 g (92% of theor.) of the target compound.LC-MS (method 2): R, = 1.05 min; MS (EIpos): m/z = 202 [M+H]+.IH-NMR (400 MHz, DMSO-D6): delta [ppm] = 2.00 (s, 3H) 2.03 (s, 3H), 2.29 (s, 3H), 4.82 (s, 2H), 5.20 (s, IH), 7.01 (s, IH), 7.13 (dd, IH), 7.21 (d, IH).
Example 144-(lH-Indazol-5-yl)-2-methyl-5-oxo-4,5,6,7-tetrahydro-lH-cyclopenta[b]pyridine-3-carbonitrile100 mg (1.026 mmol) cyclopentane-l,3-dione, 150 mg (1.026 mmol) lH-indazole-5-carbaldehyde and piperidine (0.1 ml) in ethanol (8 ml) were heated to reflux for 4 h. The mixture was then evaporated to dryness, the remaining solid was dissolved in acetic acid (8 ml), and 84 mg(1.026 mmol) 3-aminobut-2-enenitrile were added. The solution was heated to reflux for 2 h. After cooling, the mixture was evaporated to dryness again, and the remaining solid was purified by preparative RP-EtaPLC (acetonitrile/water gradient) to yield 40 mg (13% of th.) of the title com- pound.LC-MS (method 5): R, = 1.27 min; MS (ESIpos): m/z = 291 (M+Eta)+ 1H-NMR (400 MHz, DMSO-d6): delta = 12.99 (s, IH), 10.08 (s, IH), 8.02 (s, IH), 7.52 (s, IH), 7.46 (d, IH), 7.22 (dd, IH), 4.49 (s, IH), 2.69-2.56 (m, 2H), 2.26-2.23 (m, 2H), 2.12 (s, 3H) ppm
With hydrogenchloride; In ethanol; at 80℃; for 16h;Inert atmosphere;
To a solution of <strong>[5446-17-3](5-chloro-2-methylphenyl)hydrazine hydrochloride</strong> (1.49 g, 7.72 mmol, 1.00 equiv) in ethanol (8 mL) was added hydrogen chloride (4.0 mL, 20 mmol, 2 equiv, 5 M aqueous solution) and 3-aminocrotonitrile (0.664 g, 8.09 mmol, 1.05 equiv). The reaction mixture was stirred at 80 C. for 16 hours and then brought to neutral pH with saturated aqueous sodium bicarbonate solution. The resultant solution was extracted twice with dichloromethane, and the combined extracts were dried over magnesium sulfate, filtered, and concentrated to yield 1.41 g (82%) of 1-(5-chloro-2-methylphenyl)-3-methyl-1H-pyrazol-5-amine, which was carried forward without further purification. LCMS (ESI) m+H=222.2; 1H NMR (400 MHz, DMSO-d6) delta: 7.39 (d, 1H), 7.37 (d, 1H), 7.25 (s, 1H), 5.22 (s, 1H), 5.00 (s, 2H), 2.04 (overlapping s and s, 6H).
With indium(III) chloride In water at 100℃; for 0.166667h;
4.3. General procedure for synthesis of 3-(5-amino-3-methyl-1-phenyl-1H-4-pyrazolyl)-3-hydroxy-2-indolinone (13)
General procedure: A mixture of phenylhydrazine (1 mmol), 3-aminocrotononitrile (1 mmol), and InCl3 (0.1 mmol) in water (10 ml) was added to isatin (1 mmol) and the reaction mixture heated under reflux at 100 °C for 10 min. After completion of the reaction (TLC), the reaction mixture was cooled to room temperature; the precipitate was filtered off and washed with methanol to obtain pure 13 as a colorless solid. Spectroscopic data for all the compounds are given below.
With indium(III) chloride; In water; at 100℃; for 0.166667h;
General procedure: A mixture of phenylhydrazine (1 mmol), 3-aminocrotononitrile (1 mmol), and InCl3 (0.1 mmol) in water (10 ml) was added to isatin (1 mmol) and the reaction mixture heated under reflux at 100 C for 10 min. After completion of the reaction (TLC), the reaction mixture was cooled to room temperature; the precipitate was filtered off and washed with methanol to obtain pure 13 as a colorless solid. Spectroscopic data for all the compounds are given below.
With indium(III) chloride; In water; at 100℃; for 0.166667h;
General procedure: A mixture of phenylhydrazine (1 mmol), 3-aminocrotononitrile (1 mmol), and InCl3 (0.1 mmol) in water (10 ml) was added to isatin (1 mmol) and the reaction mixture heated under reflux at 100 C for 10 min. After completion of the reaction (TLC), the reaction mixture was cooled to room temperature; the precipitate was filtered off and washed with methanol to obtain pure 13 as a colorless solid. Spectroscopic data for all the compounds are given below.
With indium(III) chloride In water at 100℃; for 0.166667h;
4.3. General procedure for synthesis of 3-(5-amino-3-methyl-1-phenyl-1H-4-pyrazolyl)-3-hydroxy-2-indolinone (13)
General procedure: A mixture of phenylhydrazine (1 mmol), 3-aminocrotononitrile (1 mmol), and InCl3 (0.1 mmol) in water (10 ml) was added to isatin (1 mmol) and the reaction mixture heated under reflux at 100 °C for 10 min. After completion of the reaction (TLC), the reaction mixture was cooled to room temperature; the precipitate was filtered off and washed with methanol to obtain pure 13 as a colorless solid. Spectroscopic data for all the compounds are given below.
With indium(III) chloride In water at 100℃; for 0.166667h;
4.3. General procedure for synthesis of 3-(5-amino-3-methyl-1-phenyl-1H-4-pyrazolyl)-3-hydroxy-2-indolinone (13)
General procedure: A mixture of phenylhydrazine (1 mmol), 3-aminocrotononitrile (1 mmol), and InCl3 (0.1 mmol) in water (10 ml) was added to isatin (1 mmol) and the reaction mixture heated under reflux at 100 °C for 10 min. After completion of the reaction (TLC), the reaction mixture was cooled to room temperature; the precipitate was filtered off and washed with methanol to obtain pure 13 as a colorless solid. Spectroscopic data for all the compounds are given below.
Intermediate P : 1 -tert-Butyl-3-methyl-1 H-pyrazol-5-amine tert- Butylhydrazine hydrochloride (15.2 g, 122 mmol) was added to the aqueous solution of sodium hydroxide (60 mL, 2M, 122 mmol) and stirred until dissolution of a solid. To the mixture 3-aminobut-2-enenitrile (10 g, 122 mmol) was added. The reaction mixture was stirred while heating at 90°C for 18 hours, then cooled to room temperature and extracted with dichloromethane (3 chi 50 mL). Organic layers were combined, washed with brine, dried (Na2S04) and concentrated under reduced pressure to obtain title product as a white, amorphous solid with the yield of 92percent (17.2 g, 1 12 mmol). 1H NMR (500 MHz, CDCl3) delta 7.25 (t, J=8.3 Hz, 1 H), 6.50 (d, J=8.3 Hz, 2H), 3.88 (s, 6H).
General procedure: 3-aminocrotononitrile (48, 10 mmol) was added to a suspension of the appropriate arylhydrazine 49a-l (10 mmol) in 12M HCl-H2O (12 mL, 1:3), and the resulting mixture was heated under reflux for 12 hours and then cooled and neutralized with 2.5M sodium hydroxide solution. The suspension was extracted with CH2Cl2 (3x30 mL). The organic phases were washed with brine (20 mL), dried and the solvent evaporated in vacuo. The residue oil was triturated with hexane to obtain a solid which was separated by filtration. Subsequent chromatography was performed where indicated.
1-(4,6-dimethylpyrimidin-2-yl)-3-methyl-1H-pyrazol-5-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
In ethanol; for 3.0h;Reflux;
A mixture of <strong>[23906-13-0]2-hydrazinyl-4,6-dimethylpyrimidine</strong> (500 mg, 3.62 mmol) and 3- aminocrotononitrile (312 mg, 3.80 mmol) in ethanol (10 mL) was heated at reflux for 3 h and was then concentrated in vacuo. The crude product was recrystallized from methanol to afford 800 mg of l-(4,6-dimethylpyrimidin-2-yl)-3-methyl-lH-pyrazol-5-amine as a pale brown solid. Yield: 90%; m/z (ESI+) 226 (MNa+), 204 (MH+).
Intermediate 23-Methyl-l-(l-methylethyl)-6-oxo-6,7-dihydro-lH-pyrazolo[3,4-6]pyridine-4- carboxylic acidStep 1:3-Methyl-l-(l-methylethyl)-lH-pyrazol-5-amine3-Amino-2-butenenitrile (33.3 g, 0.41 mol) and ethanol (170 mL) were combined and stirred at room temperature for 30 min., after which time isopropylhydrazine (50 g, 0.67 mol) was added at once. After stirring at room temperature for 5 min., the contents were then heated at reflux for 10 h. After cooling to room temperature, the mixture was concentrated in vacuo to give the desired product (85 g) which was used in the next step directly. 1H NMR (400 MHz, DMSO-d6) ? ppm 1.21 (d, 6 H, J =6.4 Hz), 1.94 (s, 3H), 4.21 (m, 1H), 4.93 (s, 2H), 5.02 (s, 1H).
Stage #1: 3-Aminocrotononitrile; N-4-chlorophenylhydrazine With hydrogenchloride In water at 150℃; for 0.166667h; Microwave irradiation; Sealed tube; Green chemistry;
Stage #2: With sodium hydroxide In water for 0.0833333h; Sonication; Green chemistry;
General Procedure 1: Synthesis of N-aryl substituted 1H-pyrazole-5-amines from 3-aminocrotonitrile
General procedure: In a 2-5mL microwave vial containing a stir bar, 3-aminocrotonitrile (164 mg, 2mmol) and 5 mL of 1M HCl were combined with stirring to give a 0.4 M solution of starting material. Next, phenylhydrazine (216 mg, 2 mmol) was added to the solution. The microwave vial was then sealed with an aluminum cap and irradiated in the microwave reactor at 150 °C for 10 m with the absorbance set to “very high.” After cooling, the orange sludge-containing heterogeneous solution was basified with 10% NaOH and was sonicated for 5 m to produce a visible solid precipitate. The precipitate was filtered, washed twice with D.I. water, and then dried to yield the product as a light orange solid (292 mg, 84% yield). For compounds that do not readily precipitate, the product can be isolated by extracting the basic aqueous layer 3x with dichloromethane (DCM). The combined organic layers are dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the product.
80%
With hydrogenchloride In water for 0.416667h; Heating;
General procedure for the synthesis of 1-aryl-3-methyl-5-aminopyrazoles (3a-e).
General procedure: To a solution of the corresponding arylhydrazine (1a-e) (10 mmol) in concentrated hydrochloric acid (5 mL), 820 mg of 3-aminocrotonitrile (2) (10 mmol) was added with magnetic stirring. The mixture was left to react for 10 minutes and then more HCl was added (5 mL) while heating for 15 additional minutes. After completion of the reaction, a yellow solution was obtained which was then cooled by addition of crushed ice and neutralized with concentrated ammonium hydroxide. Finally, the formed precipitate corresponding to aminopyrazoles 3a-e, was vacuum filtered and washed with cold water.
With hydrogenchloride; In water; for 0.416667h;Heating;
General procedure: To a solution of the corresponding arylhydrazine (1a-e) (10 mmol) in concentrated hydrochloric acid (5 mL), 820 mg of 3-aminocrotonitrile (2) (10 mmol) was added with magnetic stirring. The mixture was left to react for 10 minutes and then more HCl was added (5 mL) while heating for 15 additional minutes. After completion of the reaction, a yellow solution was obtained which was then cooled by addition of crushed ice and neutralized with concentrated ammonium hydroxide. Finally, the formed precipitate corresponding to aminopyrazoles 3a-e, was vacuum filtered and washed with cold water.
General procedure: In a 2-5mL microwave vial containing a stir bar, 3-aminocrotonitrile (164 mg, 2mmol) and 5 mL of 1M HCl were combined with stirring to give a 0.4 M solution of starting material. Next, phenylhydrazine (216 mg, 2 mmol) was added to the solution. The microwave vial was then sealed with an aluminum cap and irradiated in the microwave reactor at 150 C for 10 m with the absorbance set to ?very high.? After cooling, the orange sludge-containing heterogeneous solution was basified with 10% NaOH and was sonicated for 5 m to produce a visible solid precipitate. The precipitate was filtered, washed twice with D.I. water, and then dried to yield the product as a light orange solid (292 mg, 84% yield). For compounds that do not readily precipitate, the product can be isolated by extracting the basic aqueous layer 3x with dichloromethane (DCM). The combined organic layers are dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the product.
4,4'-((propane-1,3-diylbis(oxy))bis(4,1-phenylene))bis(2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbonitrile)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With acetic acid; for 2h;Reflux;
General procedure: To a warm glacial acetic solution of dialdehyde 1 (1 mmol)was added 3-aminocrotononitrile (4 mmol). The resultingyellowish solution was refluxed for 2 h and was thenallowed to cool to room temperature (RT). Thereupon itwas poured over crushed ice and the formed precipitatewas filtered off, dried, and purified by recrystallization toafford off-white to pale yellow crystals.
63%
In acetic acid; for 2h;Reflux;
General procedure: To a warm glacial acetic solution of dialdehyde 3a-c or 9a-c (1 mmol), 3-aminocrotononitrile 4 (4 mmol) was added. The resulting yellowish solution was refluxed for 2 h and was then allowed to cool to room temperature. Thereupon it was poured over crushed ice and the formed precipitate was filtered off, dried and purified by recrystallization to afford off-white to pale yellow crystals.
2-[(5-amino-3-methyl-1H-pyrazol-4-yl)diazenyl]-5-nitrobenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
General procedure: 2 mmol of 5-nitroanthranilic acid is dissolved in hydrochloric acid (in 5 ml water). Then, the solution is cooled to 0e5 C withstirring. Sodium nitrite (2 mmol) inwater (5 ml) is gradually addedto this solution over 15 min period at 0e5 C while stirring. Thereaction mixture is stirred for 2 h at this temperature. The resultingdiazonium salt solution is then added dropwise to a well-cooledand stirred solution of malononitrile (2 mmol) in sodium acetate(2 g) dissolves in 20 mLwater. The pH is maintained at 4e6 throughthe coupling process by adding sodium acetate. Stirring iscontinued for 4 h at 0e5 C. The precipitated products diluted withcold water (50 mL), filtered off, washed with water several times,and dried. The obtained product is recrystallized from DMF-H2Omixture. Hydrazine hydrate (0.5 mL) is added to a solution of thisobtained product (3 mmol) in 20 ml ethanol. The reaction mixtureis heated under reflux for 4e6 h and then cooled at room temperature.Upon water being added, precipitate product is filtered,washed with water several times, and dried. The obtained product2-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]-5-nitrobenzoic acid (A)is recrystallized from DMF-H2O mixture.
General procedure: In a 2-5mL microwave vial containing a stir bar, 3-aminocrotonitrile (164 mg, 2mmol) and 5 mL of 1M HCl were combined with stirring to give a 0.4 M solution of starting material. Next, phenylhydrazine (216 mg, 2 mmol) was added to the solution. The microwave vial was then sealed with an aluminum cap and irradiated in the microwave reactor at 150 C for 10 m with the absorbance set to ?very high.? After cooling, the orange sludge-containing heterogeneous solution was basified with 10% NaOH and was sonicated for 5 m to produce a visible solid precipitate. The precipitate was filtered, washed twice with D.I. water, and then dried to yield the product as a light orange solid (292 mg, 84% yield). For compounds that do not readily precipitate, the product can be isolated by extracting the basic aqueous layer 3x with dichloromethane (DCM). The combined organic layers are dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the product.
General procedure: In a 2-5mL microwave vial containing a stir bar, 3-aminocrotonitrile (164 mg, 2mmol) and 5 mL of 1M HCl were combined with stirring to give a 0.4 M solution of starting material. Next, phenylhydrazine (216 mg, 2 mmol) was added to the solution. The microwave vial was then sealed with an aluminum cap and irradiated in the microwave reactor at 150 C for 10 m with the absorbance set to ?very high.? After cooling, the orange sludge-containing heterogeneous solution was basified with 10% NaOH and was sonicated for 5 m to produce a visible solid precipitate. The precipitate was filtered, washed twice with D.I. water, and then dried to yield the product as a light orange solid (292 mg, 84% yield). For compounds that do not readily precipitate, the product can be isolated by extracting the basic aqueous layer 3x with dichloromethane (DCM). The combined organic layers are dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the product.
4-(benzo[b]thiophen-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With acetic acid; In isopropyl alcohol; at 100℃; for 18h;
A mixture of thianaphthene-3-carboxaldehyde (0.5 g, 3.08 mmol), 3-aminocrotonitrile (0.554 mL, 6.74 mmol) and acetic acid (0.076 mL, 3.08 mmol) in isopropyl alcohol (10 mL) was stirred at 100C for 18 hours. The mixture was allowed to cool to RT and concentrated. The residue was basified with aq. sodium bicarbonate, and the resulting solid was filtered off and washed with cold water and ethyl ether. The desired product was obtained as a light-yellow solid (0.738 g, 82 %). 1H-NMR (400 MHz, DMSO-d6) delta = 2.06 (s, 6H), 5.00 (s, 1H), 7.36-7.46 (m, 1H), 7.65 (s, 1H), 7.89 (d, 1H), 8.03 (d, 1H), 9.67 (s, 1H). HPLC-MS: Rt 3.878 min, m/z 292.0 (MH+).
4-(benzo[b]thiophen-3-yl)-2-methyl-6-phenyl-1,4-dihydropyridine-3,5-dicarbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7%
With acetic acid; In isopropyl alcohol; at 100℃; for 16h;
A mixture of thianaphthene-3-carboxaldehyde (0.104 g, 0.64 mmol), 3-aminocrotonitrile (0.052 g, 0.64 mmol), benzoylacetonitrile (0.0897 g, 0.62 mmol) and acetic acid (0.035 mL, 0.64 mmol) in isopropyl alcohol (3.5 mL) was heated to 100C and left to stir for 16 hours. The mixture was allowed to cool to RT and concentrated. The residue was basified with aq. sodium bicarbonate, and the resulting solid was filtered off and purified by column chromatography (3:1 Hexane: Ethyl acetate) rendering a light-yellow solid (0.0162 g, 7 %). 1H-NMR (400 MHz, DMSO-d6) delta = 2.12 (s, 3H), 5.17 (s, 1H), 7.39-7.49 (m, 2H), 7.50-7.59 (m 5H), 7.78 (s, 1H), 8.01 (dd, 1H), 8.06 (dd, 1H), 9.92 (s, 1H). HPLC-MS: Rt 4.329 min, m/z 354.1 (MH+). The following examples were synthesized according to Method F.
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