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Structure of 59997-51-2 * 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 sodium hydroxide; hydroxylamine hydrochloride In water at 50℃; for 3 h;
To an aqueous solution of sodium hydroxide solution (40.00 g, 1 mol, in 200 ml of water) was added hydroxylamine hydrochloride (24.00 g, 346 mmol) and pivaloylacetonitrile (40.00 g, 320 mmol). The resulting solution was stirred at 50° C. for 3 hrs. The reaction mixture cooled and the resultant white crystalline solid filtered, washed with water and dried to provide 3-t-butylisoxazol-5-amine as a white crystalline solid (34 g, yield 76percent yield). 1H NMR (DMSO-d6) δ 6.41 (brs, 2H), 4.85 (s, 1H), 1.18(s, 9H): LC-MS (ES, m/z, M+H) 141.3.
Reference：
[1] Heterocycles, 1991, vol. 32, # 6, p. 1153 - 1158
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 3, p. 1082 - 1105
[3] Patent: US2008/261961, 2008, A1, . Location in patent: Page/Page column 16
[4] Organic Letters, 2018, vol. 20, # 9, p. 2774 - 2777
[5] Journal of Medicinal Chemistry, 2016, vol. 59, # 18, p. 8293 - 8305
[6] Chemische Berichte, 1932, vol. 65, p. 1857,1862
[7] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 18, p. 2047 - 2050
[8] Patent: WO2010/77836, 2010, A2, . Location in patent: Page/Page column 131
[9] Molecules, 2014, vol. 19, # 2, p. 2004 - 2028
[10] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 17, p. 3436 - 3441
2
[ 59997-51-2 ]
[ 59669-59-9 ]
[ 121449-41-0 ]
Reference：
[1] Dyes and Pigments, 2010, vol. 86, # 1, p. 42 - 49
3
[ 59997-51-2 ]
[ 55809-36-4 ]
Yield
Reaction Conditions
Operation in experiment
94.5%
With hydrogenchloride; sodium hydroxide; hydroxylamine sulfate; triethylamine In methanol; toluene
EXAMPLE 1 To a suspension of cyanopinacolone (75.102 g) in a mixture of anhydrous toluene (150 ml) and anhydrous methanol (26.7 ml) is introduced gaseous hydrogen chloride (26.3 g) with cooling at 5° to 10° C. and stirring, and the whole mixture is allowed to stand at 10° to 12° C. for 23 hours. To the reaction mixture is dropwise added anhydrous methanol (750 ml), then triethylamine (185.178 g) with cooling and stirring to make a complete solution. The reaction mixture is treated with hydroxylamine sulfate (51.704 g) and stirred at 50° C. for 2 hours. Then, conc. hydrochloric acid (112.629 g) is dropwise added to the mixture, which is stirred at 50° C. for 1 hour. After evaporating the solvent under reduced pressure from the reaction mixture, the residue is made alkaline with 48percent aqueous sodium hydroxide with cooling, and the aqueous solution is shaken with toluene. The organic layer is washed with water, subjected to azeotropic distillation under atmospheric pressure, and evaporated to dryness to remove the solvent, whereby 3-amino-5-t-butylisoxazole (79.480 g) is obtained. Melting point is 106° to 109° C. Yield is 94.5percent.
77%
With hydroxylamine hydrochloride; sodium hydroxide In water at 20℃; for 0.5 h;
4,4-dimethyl-3-oxopentanenitrile (3 g, 23.97 mmol) was dissolved in distilled water, stirred, and added with NaOH (1.06 g, 26.4 mmol) and NH2OH-HCl (1.83 g, 26.4 mmol). The reaction solution was stirred for about 30 minutes at room temperature. The reaction mixture was calibrated to yield pH in a range of 8 to 9 by adding an aqueous solution of 1 N NaOH, followed by further stirring for 10 hours or more at 50°C. The reaction mixture was washed 2 to 3 times with carbon tetrachloride, and aqueous layer was calibrated to yield pH in a range of 4 to 5 by adding concentrated HC1. The reaction mixture was further stirred for about 3 hours at 50°C. The reaction mixture was cooled to room temperature, and calibrated to yield pH 12 by adding an aqueous solution of 1 N NaOH. The resulting solid was filtered under reduced pressure, and washed with distilled water. The filtered solid was dried with warm wind in an oven (40°C) for 3 hours or more to obtain the title compound (2.6 g, 77percent). -NMR Spectrum (300 MHz, DMSO-i: δ 5.49 (s, 1H), 5.40 (s, 2H), 1.21 (s, 9H) MS(ESI+, m/z): 141 [M+H]+
77%
Stage #1: With hydroxylamine hydrochloride; sodium hydroxide In water at 20℃; for 0.5 h; Stage #2: With sodium hydroxide In water at 50℃;
4,4-dimethyl-3-oxopentanenitrile (3 g, 23.97 mmol) was dissolved in distilled water, stirred, and added with NaOH (1.06 g, 26.4 mmol) and NH2OH.HCl (1.83 g, 26.4 mmol). The reaction solution was stirred for about 30 minutes at room temperature. The reaction mixture was calibrated to yield pH in a range of 8 to 9 by adding an aqueous solution of 1 N NaOH, followed by further stirring for 10 hours or more at 50° C. The reaction mixture was washed 2 to 3 times with carbon tetrachloride, and aqueous layer was calibrated to yield pH in a range of 4 to 5 by adding concentrated HCl. The reaction mixture was further stirred for about 3 hours at 50° C. The reaction mixture was cooled to room temperature, and calibrated to yield pH 12 by adding an aqueous solution of 1 N NaOH. The resulting solid was filtered under reduced pressure, and washed with distilled water. The filtered solid was dried with warm wind in an oven (40° C.) for 3 hours or more to obtain the title compound (2.6 g, 77percent). 1H-NMR Spectrum (300 MHz, DMSO-d6): δ 5.49 (s, 1H), 5.40 (s, 2H), 1.21 (s, 9H) MS (ESI+, m/z): 141 [M+H]+
70%
With hydroxylamine hydrochloride; sodium hydroxide In water at 25℃; for 0.5 h;
To a solution of pivaloylacetonitrile (3 g, 23.97 mmol) in water (20 mL), NaOH (1.06 g, 26.4 mmol) and hydroxylamine hydrochloride (1.83 g, 26.4 mmol) were added continuously with stirring. The resulting solution was stirred for approximately 30 min at room temperature, and the pH adjusted to 10–11 with 1 M NaOH. After stirring for 10 h or more at 50 °C, the mixture was cooled and washed two to three times with carbon tetrachloride. The aqueous layer was acidified with concentrated HC1 until the pH = 4–5, and then further stirred for approximately 3 h at 50 °C. The reaction mixture was cooled to room temperature, and adjusted to pH 12 by adding an aqueous solution of 1 N NaOH. The resulting solid was filtered, washed with distilled water, and driedin air to obtain compound 25s as a white solid (2.0 g, yield: 70percent).
84.74%.
With hydrogenchloride; sodium hydroxide; hydroxylamine hydrochloride In ethanol
EXAMPLE 1 In a mixture of pivaloylacetonitrile (25.03 g) and 50percent (v/v) ethanol (400 ml) is dissolved 96percent sodium hydroxide (9.583 g). To this solution is added hydroxylamine hydrochloride (purity, 96percent) at 27° C. to give a solution (pH 7.8), which is stirred at 60° C. for 22 hours. The reaction mixture is cooled at 20° C., mixed with conc. hydrochloric acid (9.11 g), and stirred at 50° C. for 2 hours. Conc. hydrochloric acid (14.18 g) is added to the mixture, which is refluxed at 100° C. for 1 hour. The reaction mixture is concentrated under reduced pressure to remove ethanol and the residue is mixed with 30percent sodium hydroxide (62 g). The mixture is shaken with chloroform. The chloroform layer is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3-amino-5-t-butylisoxazole (23.76 g). Yield, 84.74percent. m.p. 101-109.5° C. Purity, 95.1percent.
Reference：
[1] Patent: US4200757, 1980, A,
[2] Patent: WO2013/100632, 2013, A1, . Location in patent: Page/Page column 42; 43
[3] Patent: US2014/371219, 2014, A1, . Location in patent: Paragraph 0288; 0289; 0290
[4] Molecules, 2014, vol. 19, # 2, p. 2004 - 2028
[5] Heterocycles, 1991, vol. 32, # 6, p. 1153 - 1158
[6] Patent: US4256899, 1981, A,
[7] Patent: US4500345, 1985, A,
[8] Journal of Medicinal Chemistry, 2016, vol. 59, # 18, p. 8293 - 8305
Stage #1: With sodium hydride In 1,4-dioxane; paraffin oil (nujol) for 0.75 h; Stage #2: for 3 h; Reflux
NaH (50 percent in paraffin oil) (1.2 eq., 4.6 g) was dissolved in 1 ,4-dioxane (120 ml) and the mixture was stirred for a few minutes. Acetonitrile (1.2 eq., 4.2 g) was added dropwise within 15 min and the mixture was stirred for a further 30 min. The methyl pivalate (J-I) (1 eq., 10 g) was added dropwise within 15 min and the reaction mixture was refluxed for 3 h. After complete reaction, the reaction mixture was placed in iced water (200 g), acidified to pH 4.5 and extracted with dichloromethane (12 x 250 ml). The combined organic phases were dried over sodium sulphate, distilled and after recrystallisation from hexane (100 ml) 5 g of the product (J-Il) (51 percent yield) was able to be obtained as a solid brown substance.
51%
Stage #1: With sodium hydride In 1,4-dioxane; paraffin oil (nujol) for 0.75 h; Stage #2: for 3 h; Reflux
NaH (50 percent in paraffin oil) (1.2 eq., 4.6 g) was dissolved in 1 ,4-dioxane (120 ml) and the mixture was stirred for a few minutes. Acetonitrile (1.2 eq., 4.2 g) was added dropwise within 15 min and the mixture was stirred for a further 30 min. The methyl pivalate (J-I) (1 eq., 10 g) was added dropwise within 15 min and the reaction mixture was refluxed for 3 h. After complete reaction, the reaction mixture was placed in iced water (200 g), acidified to pH 4.5 and extracted with dichloromethane (12 x 250 ml). The combined organic phases were dried over sodium sulphate, distilled and after recrystallisation from hexane (100 ml) 5 g of the product (J-Il) (51 percent yield) was able to be obtained as a solid brown substance.
51%
Stage #1: With sodium hydride In 1,4-dioxane; paraffin oil for 0.75 h; Stage #2: for 3 h; Reflux
NaH (50percent in paraffin oil) (1.2 equiv., 4.6 g) was dissolved in 1,4-dioxane (120 mL) and stirred for a few minutes. Acetonitrile (1.2 equiv., 4.2 g) was added dropwise within 15 min and the mixture was stirred for a further 30 min. The methyl pivalate (J-I) (1 equiv., 10 g) was added dropwise within 15 min and the reaction mixture was refluxed for 3 h. After complete conversion the reaction mixture was poured into iced water (200 g), acidified to pH 4.5, and extracted with dichloromethane (12.x.250 mL). The combined organic phases were dried over sodium sulphate, distilled, and after recrystallisation from hexane (100 mL) 5 g of the product (J-II) (51percent yield) was obtained as a brown solid substance.
51%
Stage #1: With sodium hydride In 1,4-dioxane; paraffin oil (nujol) for 0.75 h; Stage #2: Reflux
Step j02: NaH (50percent in paraffin oil) (1.2 eq., 4.6 g) was dissolved in 1,4-dioxane (120 ml) and the mixture was stirred for a few minutes. Acetonitrile (1.2 eq., 4.2 g) was added dropwise within 15 min and the mixture was stirred for a further 30 min. The methyl pivalate (J-I) (1 eq., 10 g) was added dropwise within 15 min and the reaction mixture was refluxed for 3 h. After complete reaction, the reaction mixture was placed in iced water (200 g), acidified to pH 4.5 and extracted with dichloromethane (12.x.250 ml). The combined organic phases were dried over sodium sulphate, distilled and after recrystallisation from hexane (100 ml) 5 g of the product (J-II) (51percent yield) was able to be obtained as a solid brown substance.
51%
Stage #1: With sodium hydride In 1,4-dioxane; paraffin oil (nujol) for 0.75 h; Stage #2: for 3.25 h; Reflux
NaH (50 percent in paraffin oil) (1.2 eq., 4.6 g) was dissolved in 1 ,4-dioxane (120 ml) and the mixture was stirred for a few minutes. Acetonitrile (1.2 eq., 4.2 g) was added dropwise within 15 min and the mixture was stirred for a further 30 min. The methyl pivalate (J-l) (1 eq., 10 g) was added dropwise within 15 min and the reaction mixture was refluxed for 3 h. After complete reaction, the reaction mixture was placed in iced water (200 g), acidified to pH 4.5 and extracted with dichloromethane (12 x 250 ml). The combined organic phases were dried over sodium sulphate, distilled and after recrystallisation from hexane (100 ml) 5 g of the product (J-ll) (51 percent yield) was able to be obtained as a solid brown substance
51%
Stage #1: With sodium hydride In 1,4-dioxane; paraffin oil (nujol) for 0.5 h; Stage #2: for 3 h; Reflux
Step j02: NaH (50percent in paraffin oil) (1.2 eq., 4.6 g) was dissolved in 1,4-dioxane (120 ml) and the mixture was stirred for a few minutes. Acetonitrile (1.2 eq., 4.2 g) was added dropwise within 15 min and the mixture was stirred for a further 30 min. The methyl pivalate (J-I) (1 eq., 10 g) was added dropwise within 15 min and the reaction mixture was refluxed for 3 h. After complete reaction, the reaction mixture was placed in iced water (200 g), acidified to pH 4.5 and extracted with dichloromethane (12.x.250 ml). The combined organic phases were dried over sodium sulfate, distilled and after recrystallisation from hexane (100 ml) 5 g of the product (J-II) (51percent yield) was able to be obtained as a solid brown substance.
51%
Stage #1: With sodium hydride In 1,4-dioxane; paraffin oil for 0.75 h; Stage #2: for 3 h; Reflux
NaH (50 percent in paraffin oil) (1.2 equivalents, 4.6 g) was dissolved in 1 ,4-dioxane (120 mL) and the mixture was stirred for a few minutes. Acetonitrile (1.2 equivalents, 4.2 g) was added dropwise within 15 min and the mixture was stirred for a further 30 min. The methyl pivalate (J-l) (1 equivalents, 10 g) was added dropwise within 15 min and the reaction mixture was refluxed for 3 h. After complete reaction, the reaction mixture was placed in iced water (200 g), acidified to pH 4.5 and extracted with dichloromethane (12 x 250 mL). The combined organic phases were dried over sodium sulphate, distilled and after recrystallisation from n-hexane (100 mL) 5 g of the product (J-ll) (51 percent yield) was able to be obtained as a solid brown substance.
51%
Stage #1: With sodium hydride In 1,4-dioxane; paraffin oil for 0.75 h; Stage #2: for 3 h; Reflux
Step j02 NaH (50percent in paraffin oil) (1.2 equivalents, 4.6 g) was dissolved in 1,4-dioxane (120 mL) and the mixture was stirred for a few minutes. Acetonitrile (1.2 equivalents, 4.2 g) was added dropwise within 15 min and the mixture was stirred for a further 30 min. The methyl pivalate (J-I) (1 equivalents, 10 g) was added dropwise within 15 min and the reaction mixture was refluxed for 3 h. After complete reaction, the reaction mixture was placed in iced water (200 g), acidified to pH 4.5 and extracted with dichloromethane (12*250 mL). The combined organic phases were dried over sodium sulfate, distilled and after recrystallisation from n-hexane (100 mL) 5 g of the product (J-II) (51percent yield) was able to be obtained as a solid brown substance.
51%
Stage #1: With sodium hydride In 1,4-dioxane; paraffin oil for 0.75 h; Stage #2: for 3.25 h; Reflux
NaH (50 percent in paraffin oil) (1 .2 equivalents, 4.6 g) was dissolved in 1 ,4-dioxane (120 mL) and the mixture was stirred for a few minutes. Acetonitrile (1 .2 equivalents, 4.2 g) was added dropwise within 15 min and the mixture was stirred for a further 30 min. The methyl pivalate (J-l) (1 equivalents, 10 g) was added dropwise within 15 min and the reaction mixture was refluxed for 3 h. After complete reaction, the reaction mixture was placed in iced water (200 g), acidified to pH 4.5 and extracted with dichloromethane (12 x 250 mL). The combined organic phases were dried over sodium sulphate, distilled and after recrystallisation from n-hexane (100 mL) 5 g of the product (J-ll) (51 percent yield) was able to be obtained as a solid brown substance.
51%
Stage #1: With sodium hydride In 1,4-dioxane; paraffin oil for 0.75 h; Stage #2: for 3.25 h; Reflux
Step j02: NaH (50 percent in paraffin oil) (1 .2 equivalents, 4.6 g) was dissolved in 1 ,4-dioxane (120 mL) and the mixture was stirred for a few minutes. Acetonitrile (1 .2 equivalents, 4.2 g) was added dropwise within 15 min and the mixture was stirred for a further 30 min. The methyl pivalate (J-l) (1 equivalents, 10 g) was added dropwise within 15 min and the reaction mixture was refluxed for 3 h. After complete reaction, the reaction mixture was placed in iced water (200 g), acidified to pH 4.5 and extracted with dichloromethane (12 x 250 mL). The combined organic phases were dried over sodium sulphate, distilled and after recrystallisation from n-hexane (100 mL) 5 g of the product (J-ll) (51 percent yield) was able to be obtained as a solid brown substance.
51%
Stage #1: With sodium hydride In 1,4-dioxane; paraffin oil for 0.75 h; Stage #2: for 3.25 h; Reflux
Step j02: NaH (50 percent in paraffin oil) (1 .2 equivalents, 4.6 g) was dissolved in 1 ,4-dioxane (120 mL) and the mixture was stirred for a few minutes. Acetonitrile (1 .2 equivalents, 4.2 g) was added dropwise within 15 min and the mixture was stirred for a further 30 min. The methyl pivalate (J-l) (1 equivalents, 10 g) was added dropwise within 15 min and the reaction mixture was refluxed for 3 h. After complete reaction, the reaction mixture was placed in iced water (200 g), acidified to pH 4.5 and extracted with dichloromethane (12 x 250 mL). The combined organic phases were dried over sodium sulphate, distilled and after recrystallisation from n-hexane (100 mL) 5 g of the product (J-ll) (51 percent yield) was able to be obtained as a solid brown substance.
51%
Stage #1: With sodium hydride In 1,4-dioxane; paraffin oil for 0.75 h; Stage #2: for 3.25 h; Reflux
NaH (50 percent in paraffin oil) (1 .2 equivalents, 4.6 g) was dissolved in 1 ,4-dioxane (120 mL) and the mixture was stirred for a few minutes. Acetonitrile (1 .2 equivalents, 4.2 g) was added dropwise within 15 min and the mixture was stirred for a further 30 min. The methyl pivalate (J-l) (1 equivalents, 10 g) was added dropwise within 15 min and the reaction mixture was refluxed for 3 h. After complete reaction, the reaction mixture was placed in iced water (200 g), acidified to pH 4.5 and extracted with dichloromethane (12 x 250 mL). The combined organic phases were dried over sodium sulphate, distilled and after recrystallisation from n-hexane (100 mL) 5 g of the product (J-ll) (51 percent yield) was able to be obtained as a solid brown substance
51%
Stage #1: With sodium hydride In 1,4-dioxane; paraffin oil for 0.75 h; Stage #2: for 3 h; Reflux
Step j02: NaH (50 percent in paraffin oil) (1 .2 equivalents, 4.6 g) was dissolved in 1 ,4-dioxane (120 mL) and the mixture was stirred for a few minutes. Acetonitrile (1 .2 equivalents, 4.2 g) was added dropwise within 15 min and the mixture was stirred for a further 30 min. The methyl pivalate (J-l) (1 equivalents, 10 g) was added dropwise within 15 min and the reaction mixture was refluxed for 3 h. After complete reaction, the reaction mixture was placed in iced water (200 g), acidified to pH 4.5 and extracted with dichloromethane (12 x 250 mL). The combined organic phases were dried over sodium sulphate, distilled and after recrystallisation from n-hexane (100 mL) 5 g of the product (J-ll) (51 percent yield) was able to be obtained as a solid brown substance.
Reference：
[1] Tetrahedron, 1993, vol. 49, # 23, p. 5091 - 5098
[2] Journal of the Chemical Society, Chemical Communications, 1992, # 1, p. 50 - 51
[3] Patent: WO2010/127855, 2010, A1, . Location in patent: Page/Page column 95
[4] Patent: WO2010/127856, 2010, A1, . Location in patent: Page/Page column 78
[5] Patent: US2012/46301, 2012, A1, . Location in patent: Page/Page column 28; 29
[6] Patent: US2012/115903, 2012, A1, . Location in patent: Page/Page column 33
[7] Patent: WO2012/62462, 2012, A1, . Location in patent: Page/Page column 73
[8] Patent: US2012/115893, 2012, A1, . Location in patent: Page/Page column 29
[9] Patent: WO2013/13815, 2013, A1, . Location in patent: Page/Page column 104
[10] Patent: US2013/29962, 2013, A1, . Location in patent: Paragraph 0667
[11] Patent: WO2013/68463, 2013, A1, . Location in patent: Page/Page column 46
[12] Patent: WO2013/68461, 2013, A1, . Location in patent: Page/Page column 67
[13] Patent: WO2013/68467, 2013, A1, . Location in patent: Page/Page column 48
[14] Patent: WO2013/68464, 2013, A1, . Location in patent: Page/Page column 48
[15] Patent: WO2013/68462, 2013, A1, . Location in patent: Page/Page column 56
[16] Patent: WO2012/62463, 2012, A1, . Location in patent: Page/Page column 72
[17] Patent: WO2016/3827, 2016, A2, . Location in patent: Paragraph 0219
7
[ 75-97-8 ]
[ 59997-51-2 ]
Yield
Reaction Conditions
Operation in experiment
85%
With hydrogenchloride; sodium hydroxide; sodium bicarbonate; chlorine In methanol; water; benzene
EXAMPLE 2 To a solution of pinacolone (100.16 g, 1 mol) in methanol (300 ml) is introduced gaseous chlorine (70.91 g, 1 mol) at 15-20° C. over a period of 1 hour. The reaction mixture is neutralized with a 48percent solution of sodium hydroxide in methanol (285 ml) and then aqueous solution of sodium hydrogen carbonate (4.20 g) in that order. After dilution with methanol (40 ml), the resulting mixture is mixed with an aqueous solution (137 ml) of sodium cyanide (58.81 g, 1.2 mol) and refluxed for 1 hour. The methanol is evaporated under atmospheric pressure over a period of 1.5 hours. The residue is mixed with a 4percent aqueous sodium hydroxide (650 g) solution and shaken with benzene (300 ml) to remove neutral material (10.78 g). Hydrochloric acid (35percent) (92.60 g) is poured into said alkaline aqueous layer below 15° C., and the mixture is shaken with benzene (750 ml). The benzene layer is washed with water, then mixed with an aqueous solution (44 ml) of sodium hydrogen carbonate (0.66 g), and the benzene layer is evaporated under atmospheric pressure. A solution of the residue is adjusted to pH 7.0 by stirring with benzene (142 ml), water (30 ml) then 35percent hydrochloric acid (0.37 g). The benzene layer is dried and concentrated to give cyanopinacolone (106.70 g) as crystals melting at 64° to 67° C. Yield is 85 percent.
Reference：
[1] Patent: US4186144, 1980, A,
[2] Chemische Berichte, 1911, vol. 44, p. 2071
8
[ 773837-37-9 ]
[ 5469-26-1 ]
[ 59997-51-2 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2014, vol. 78, p. 294 - 303
[2] Tetrahedron Letters, 2019, vol. 60, # 1, p. 72 - 74
9
[ 598-98-1 ]
[ 59997-51-2 ]
Reference：
[1] Patent: US4716237, 1987, A,
[2] Patent: US4716237, 1987, A,
[3] Patent: US4416683, 1983, A,
[4] Patent: US4781750, 1988, A,
10
[ 13547-70-1 ]
[ 59997-51-2 ]
Reference：
[1] Patent: US4186144, 1980, A,
11
[ 3282-30-2 ]
[ 372-09-8 ]
[ 59997-51-2 ]
Reference：
[1] Synthesis, 1983, vol. No. 4, p. 308 - 309
[2] Patent: US5804532, 1998, A,
12
[ 64214-60-4 ]
[ 75-05-8 ]
[ 59997-51-2 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 7, p. 1969 - 1973
13
[ 773837-37-9 ]
[ 13547-70-1 ]
[ 59997-51-2 ]
Reference：
[1] Organic Preparations and Procedures International, 2014, vol. 46, # 4, p. 386 - 389
14
[ 3938-95-2 ]
[ 75-05-8 ]
[ 59997-51-2 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1989, vol. 26, p. 1575 - 1578
[2] Journal of Medicinal Chemistry, 2008, vol. 51, # 15, p. 4672 - 4684
[3] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 17, p. 3436 - 3441
[4] Journal of Medicinal Chemistry, 2016, vol. 59, # 18, p. 8293 - 8305
General procedure: A solution of the corresponding substituted phenylhydrazine hydrochloride (1 equiv.) and pivaloylacetonitrile (1.2 equiv.) was stirred overnight at 80 °C in ethanol. The solution was extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered, and evaporated to dryness.#10;#10;
79%
With hydrogenchloride In ethanol for 48 h; Reflux
General procedure: A solution of 4-tolyllhydrazine hydrochloride(5.20 g, 33 mmol) and pentylacyl acetonitrile (3.75 g, 30 mmol) in 0.4 M ethanolic solution of HCl(100 mL) was heated under reflux during 48 h. After cooling to room temperature, 1M NaOH wasadded to the mixture until the pH reached 10–11. The mixture was partitioned between water and ethylacetate. The water phase was extracted twice with dichloromethane. The organic phases werecombined and washed with water and brine, then dried with Na2SO4. Evaporation of the solvent invacuo afforded the crude product, which was subjected to recrystallization from ethyl acetate andpetroleum ether to produce compound 25a as a white solid (5.88 g, 86percent yield).
Reference：
[1] Molecules, 2016, vol. 21, # 5,
[2] Molecules, 2014, vol. 19, # 2, p. 2004 - 2028
[3] Journal of Medicinal Chemistry, 2002, vol. 45, # 14, p. 2994 - 3008
[4] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2013, vol. 52, # 6, p. 818 - 823
27
[ 59997-51-2 ]
[ 536-89-0 ]
[ 898537-77-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2009, vol. 52, # 13, p. 3915 - 3926
[2] Journal of the American Chemical Society, 2009, vol. 131, # 37, p. 13286 - 13296
[3] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 6, p. 1772 - 1777
[4] Patent: US2009/131437, 2009, A1, . Location in patent: Page/Page column 21
[5] MedChemComm, 2016, vol. 7, # 7, p. 1421 - 1428
28
[ 59997-51-2 ]
[ 637-60-5 ]
[ 285984-25-0 ]
Yield
Reaction Conditions
Operation in experiment
86%
With hydrogenchloride In ethanol for 48 h; Reflux
A solution of 4-tolyllhydrazine hydrochloride(5.20 g, 33 mmol) and pentylacyl acetonitrile (3.75 g, 30 mmol) in 0.4 M ethanolic solution of HCl(100 mL) was heated under reflux during 48 h. After cooling to room temperature, 1M NaOH wasadded to the mixture until the pH reached 10–11. The mixture was partitioned between water and ethylacetate. The water phase was extracted twice with dichloromethane. The organic phases werecombined and washed with water and brine, then dried with Na2SO4. Evaporation of the solvent invacuo afforded the crude product, which was subjected to recrystallization from ethyl acetate andpetroleum ether to produce compound 25a as a white solid (5.88 g, 86percent yield).
86.4%
With hydrogenchloride In ethanol at 80℃; for 8 h;
A solution of 4-tolyllhydrazine hydrochloride (5.20 g,33 mmol) and pentylacyl acetonitrile (3.75 g, 30 mmol) in 0.4 M ethanolic solution of HCl (100 mL)was heated under reflux during 8 h. After cooling to room temperature, 1 M NaOH was added to the mixture until the pH reached 10–11. The mixture was partitioned between water and ethyl acetate. The water phase was extracted twice with dichloromethane. The organic phases were combined and washed with water and brine, then dried with Na2SO4. Evaporation of the solvent in vacuo afforded the crude product, which was subjected to recrystallization from ethyl acetate and petroleum ether to produce compound 2a as a white solid (5.88 g,). Yield: 86.4percent. 1H-NMR (CDCl3, 400 MHz), δ: 7.40 (d, 2H),7.25 (d, 2H), 5.50 (s, 1H), 4.72 (brs, 2H), 2.37 (s, 3H), 1.32 (s, 9H). ESI-MS (+Q, m/z): 230 [M + H]+,252 [M + Na]+.
52%
With hydrogenchloride In ethanol; waterReflux
Intermediate A: 3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-amine To a stirred solution of p-tolylhydrazine hydrochloride (100 g, 630 mmol) in EtOH (1251 mL) was added 4,4-dimethyl-3-oxopentanenitrile (88 g, 699 mmol) and HCl (62.5 mL, 750 mmol). The resulting mixture was stirred at reflux overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo to c.a. 1/3 of the original volume. The reaction mixture was then cooled in an ice-bath and taken to c.a. pH 8-9 with 6M aq NaOH. The reaction mixture was extracted with diethyl ether (500 mL) and the organic phase washed with water (2*300 mL) before being dried over magnesium sulphate and concentrated in vacuo to afford an orange solid. The solid was suspended in iso-hexane and stirred at reflux for 2.5 h before being cooled and filtered whilst still hot to yield the subtitle product 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine as a pale brown solid (76.5 g, 52percent); Rt 1.31 min (Method 1); m/z 230 (M+H)+ (ES+); 1H NMR δ: 1.20 (9H, s), 2.32 (3H, s), 5.10 (2H, br s), 5.35 (1H, s), 7.24 (2H, d), 7.42 (2H, m).
30 g
for 1.5 h;
Pivaloylacetonitrile (19.0 g) was refluxed with tolylhydrazine hydrochloride (24.0 g) in ethanol (190 ml) for 1.5 hr. The solution was cooled and volatiles removed in vacuo. The residue was extracted with ethyl acetate and 10percent aq. sodium carbonate, and the organic layer washed with water and brine. Drying over sodium sulfate and solvent removal afforded pyrazole 6 as an off-white solid (30 g).
Reference：
[1] Patent: US2004/192653, 2004, A1,
[2] Molecules, 2014, vol. 19, # 2, p. 2004 - 2028
[3] Molecules, 2015, vol. 20, # 9, p. 16604 - 16619
[4] Organic Process Research and Development, 2010, vol. 14, # 3, p. 650 - 656
[5] Journal of the American Chemical Society, 2009, vol. 131, # 37, p. 13286 - 13296
[6] Organic Process Research and Development, 2011, vol. 15, # 4, p. 841 - 854
[7] Patent: US2015/232450, 2015, A1, . Location in patent: Paragraph 0205-0206
[8] Journal of Medicinal Chemistry, 2002, vol. 45, # 14, p. 2994 - 3008
[9] Patent: US2008/207647, 2008, A1, . Location in patent: Page/Page column 18
[10] Patent: US2015/183777, 2015, A1, . Location in patent: Paragraph 0191; 0192
[11] Molecules, 2016, vol. 21, # 5,
29
[ 59997-51-2 ]
[ 539-44-6 ]
[ 285984-25-0 ]
Yield
Reaction Conditions
Operation in experiment
80.3%
With hydrogenchloride In ethanol for 8 h; Reflux
In a 250 mL pre-flask was added 100 mL of ethanol,(30 mmol) of pivaloylacetonitrile,(33. 63 mmol) of 4-methylphenylhydrazine,3. 6 mL of concentrated hydrochloric acid was added dropwise with stirring, heated under reflux for 8 hours,Cooled, concentrated, the residue adjusted with dilute sodium hydroxide PH10-11,Extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, concentrated,The resulting solid was recrystallized from ethyl acetate / petroleum ether to give white crystals C,Yield 80.3percent. 5-tert-butyl-2-p-methylphenyl-3-aminopyrazole (3. 5 mmolC) was placed in 100 ml three-necked flask and dissolved in 30 ml of tetrahydrofuran. The three-necked flask was allowed to cool to -20 ° C, stirring in batches by adding 2. 9g sodium bicarbonate, 15min, dropwise dropwise chloroformic acid trichloroethyl ester(3. 5 mmol),Control solution temperature does not exceed ° C,After completion of the dropwise addition, the mixture was stirred for 30 min and then heated to 0 ° C for 12 h. After completion of the reaction, the mixture was filtered and the residue was rinsed with ethyl acetate and the filtrate was concentrated to yield 85percent.
80.3%
With hydrogenchloride In ethanol; water for 8 h; Reflux
In a 250 mL round botom flask, 100 mL of ethanol was added, (30 mmol) of pivaloylacetonitrile, (33.63 mmol) of 4-methylphenylhydrazine, A solution of 3.6 mL of concentrated hydrochloric acid was added dropwise with stirring,Heated to reflux for 8 hours, cool down, concentrate, The residue was adjusted to pH 10-11 with dilute sodium hydroxide, Extracted three times with ethyl acetate, Dried over anhydrous sodium sulfate, concentrate, The resulting solid was recrystallized from ethyl acetate / petroleum ether to give white crystals C, Yield 80.3percent. 5-tert-butyl-2-p-methylphenyl-3-aminopyrazole (3.5 mmolC) was placed in a 100 ml three-Dissolved in 30 ml of tetrahydrofuran, Place the three-necked flask in a cryogenic tank to cool to -20 ° C, 2.9 g of sodium bicarbonate was added in portions with stirring, After 15 min, A solution of trichloroethyl chloroformate (3.5 mmol) was added dropwise, Control the solution temperature does not exceed 0 deg C, After dripping, Continue stirring for 30min, And then heated to 0 ° C for 12 h. After completion of the reaction, The mixture is filtered, The residue was washed with ethyl acetate, The filtrate was concentrated, Yield 85percent.
80.3%
for 8 h; Reflux
In 250 ml bottle eggplant adding 100 ml ethanol, (30mmol) special fifth heavenly stem acyl acetonitrile, (33.63mmol) 4 - methyl phenyl hydrazine, stirring next adds by drops 3.6 ml concentrated hydrochloric acid, heating reflux for 8 hours, cooling, concentrated, the residue with dilute sodium hydroxide to adjust the pH 10 - 11, ethyl acetate extraction three times, dried with anhydrous sodium sulfate, concentrated, the obtained solid ethyl acetate/petroleum ether recrystallization to obtain white crystal C, yield 80.3percent. 5 - tert-butyl -2 - methylphenyl -3 - amino pyrazole (3.5mmolC) in 100 ml in three-necked bottle, to 30 ml tetrahydrofuran is dissolved, the low temperature troughthree-necked bottle is lowering the temperature to -20 °C, stirring in batches under the adding 2.9g sodium bicarbonate, 15min after, little by chlorination formic acid trichloroethyl (3.5mmol), control solution at a temperature of not more than 0 °C, after dropping, continuing to stir 30min, then heating up to 0 °C reaction 12h. The completion of the reaction, the mixture filtration, the filter residue washed ethyl acetate, the filtrate is concentrated, yield 85percent.
Reference：
[1] Patent: CN106518767, 2017, A, . Location in patent: Paragraph 0075; 0076; 0115
[2] Patent: CN106518766, 2017, A, . Location in patent: Paragraph 0098
[3] Patent: CN106518858, 2017, A, . Location in patent: Paragraph 0076
[4] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 6, p. 1772 - 1777
[5] Patent: US2009/131437, 2009, A1, . Location in patent: Page/Page column 15
[6] Patent: EP1698335, 2006, A1, . Location in patent: Page/Page column 42
[7] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 19, p. 5401 - 5409
[8] MedChemComm, 2016, vol. 7, # 7, p. 1421 - 1428
30
[ 59997-51-2 ]
[ 285984-25-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 18, p. 4383 - 4388
31
[ 59997-51-2 ]
[ 24424-99-5 ]
[ 637-60-5 ]
[ 285983-48-4 ]
Reference：
[1] Patent: US6492529, 2002, B1,
32
[ 59997-51-2 ]
[ 285983-48-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2002, vol. 45, # 14, p. 2994 - 3008
[2] Patent: US2012/184735, 2012, A1,
With hydroxylamine hydrochloride; sodium hydroxide; In water; at 60℃; for 3h;
A solution of sodium hydroxide (250g. 6.25 mol) in water (1250 ml) was added with pivaloylacetonitrile (CAS: 59997-51-2, 250g, 2.0 mol) followed by hydroxylaminehydrochloride (150g, 2.16 mol). The mixture was heated to 60 C during which time it became homogeneous and then began to deposit a solid. After 3h the mixture was cooled to RT and the solid removed by filtration, washed well with water and dried at 45C under vacuum to give the title compound (245.1g. 88%). The aqueous filtrate was extracted with DCM (2 x 100 ml) and the combined DCM layers were dried (Na2SO4) and evaporated.(10.9g,4%).?H NMR (300MHz, CDC13) 1.28 (9H, s), 4.31 (2H, br s), 5.03 (111, s).
76%
With sodium hydroxide; hydroxylamine hydrochloride; In water; at 50℃; for 3h;
To an aqueous solution of sodium hydroxide solution (40.00 g, 1 mol, in 200 ml of water) was added hydroxylamine hydrochloride (24.00 g, 346 mmol) and pivaloylacetonitrile (40.00 g, 320 mmol). The resulting solution was stirred at 50 C. for 3 hrs. The reaction mixture cooled and the resultant white crystalline solid filtered, washed with water and dried to provide 3-t-butylisoxazol-5-amine as a white crystalline solid (34 g, yield 76% yield). 1H NMR (DMSO-d6) delta 6.41 (brs, 2H), 4.85 (s, 1H), 1.18(s, 9H): LC-MS (ES, m/z, M+H) 141.3.
With hydroxyammonium sulfate; sodium hydroxide; In water; for 2h;Reflux;
Step 1: Synthesis of 3-tert-butyl-isoxazol-5-ylamine; Hydroxylamine sulfate (27.575g, 0.168mol) is added to a stirred solution of 4,4-dimethyl-3- oxopentanenitrile (2Og; O.lOmol) and sodium hydroxide (26.24g; 0.656mol) in water (16OmL). The mixture is heated at reflux for 2 hours, then allowed to cool to room temperature and extracted with methylene chloride. The combined organics are washed with water, dried (Na2SO4), filtered and concentrated in vacuo to afford title compound as a white solid. ESI m/z 141 [M+H]+
With hydroxylamine hydrochloride; sodium hydroxide; In water; at 50℃; for 3h;
To an aqueous solution of sodium hydroxide solution (0.84 g,21 mmol) in water (10 mL), pivaloylacetonitrile (1.25 g, 10 mmol) and hydroxylamine hydrochloride(0.76 g, 11 mmol) were added. The resulting solution was stirred at 50 C for 3 h. The reaction mixture was cooled and the resultant white crystalline solid was filtered, washed with water and dried to provide compound 25r as a white crystalline solid (1.23 g, yield 88%).
To a solution of 12.5 g (0.1 mol) of 4,4-dimethyl-3-oxopentanenitrile in 50 cm3 of n-propanol were added, at room temperature, 4.6 g (0.1 mol) of methylhydrazine. The reaction medium was maintained at reflux for 1 hour and then cooled to room temperature. The white solid obtained was filtered off on a sinter funnel and then washed with isopropyl ether. After drying under vacuum at 40 C., 10 g of the expected product were obtained in the form of a beige solid, the melting point of which was 157 C.
General procedure: A solution of pivoloylacetonitrile 4 (1.0 g, 8.0 mmol). substituted phenylhydrazine hydrochlorides (0.83 mL, 8.39 mmol) and a few drops of glacial acetic acid in ethanol were refluxed in absolute alcohol overnight. The solvent was evaporated by vacuum distillation and the residue was washed with petroleum ether. The solid was taken in ethyl acetate and washed with aqueous NaHCO3. The organic layer was further washed with brine, water and evaporated to yield the desired product as a crystalline solid in 80-90% yield (~ 89% )24.
A solution of ethyl 2-hydrazinylacetate hydrochloride (1.0 g, 6.5 mmol) and DIEA (1.24 mL, 7.5 mmol) in toluene was stirred at room temperature. After 15 min, 4,4-dimethyl-3-oxopentanenitrile (937 mg, 7.5 mmol) was added, and the reaction was stirred at reflux overnight. After cooling, water was added and the resulting mixture was extracted with EtOAc (x3). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum to give 1.5 g of 35 as a brown solid. This material was used without further purification.
In methanol at 120℃; for 0.666667h; microwave irradiation;
91%
With toluene-4-sulfonic acid In ethanol for 4h; Heating;
89%
In toluene Heating;
89%
Stage #1: trimethylacetylacetonitrile; phenylhydrazine With hydrogenchloride In water at 150℃; for 0.166667h; Sealed tube; Microwave irradiation; Green chemistry;
Stage #2: With sodium hydroxide In water Green chemistry;
General Procedure 2: Synthesis of 1H-pyrazole-5-amines from α-cyanoketones and phenylhydrazine
In a 2-5 mL microwave vial containing a stir bar, 3-oxo-3-phenylpropanenitrile (290 mg, 2 mmol) and 5mL of 1M HCl were combined with stirring to give a 0.4 M solution of starting material. Next, phenylhydrazine (216 mg, 2mmol) 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 resulting solution was basified with 10% NaOH and was sonicated for 5 min. 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 brown solid (365 mg, 78% yield).
81%
In ethanol at 90℃; for 7h;
76.1%
With hydrogenchloride In water at 70℃; for 2h;
2.2.1. Synthesis of 3-tert-butyl-1-phenyl-1H-pyrazole-5-amine (1)
Compound 1 was synthesized by following reported methodologies[8,9]. Phenylhydrazine (2.1220 g, 19.62 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.8502 g, 14.78 mmol) were addedinto a solution of concentrated hydrochloric acid (4 mL) in water(32 mL). The mixture was heated to 70 C under constant stirringfor 1 h. Then, concentrated hydrochloric acid (4 mL) was added andthe mixture was further heated for 1 h. The reaction mixture wascooled in an ice bath and the solution was neutralized withammonium hydroxide, with the formation of a precipitate. Thesolid formed was filtered under vacuum and washed with water(5 50 mL). The starting precursor 1 was obtained in 76.1% yield asa light brown solid. Anal. Calc. for C13H17N3: C% 72.52, H% 7.96; N%19.52. Found: C% 72.78, H% 7.65; N% 19.65. IR (Κr, cm1): nas NH23440, ns NH2 3301,CeH 3062, nas CH3 2962, ns CH3 2869, n C]N1623, n C]C 1565 cm1, das CH3 1376, t CeH 756, u C]C 698. 1HNMR (DMSO-d6): d 1.32 (s, 9H) H-5; 3.74 (s, 2H) NH2; 5.51 (s, 1H) H-6; 7.30 (t, 1H) H-11; 7.45 (t, 2H) H-10; 7.54 (d, 2H) H-9 ppm. 13CNMR (DMSO-d6): d 30.0 (C-5); 32.4 (C-4); 90.4 (C-6); 122.1 (C-9);124.9 (C-10); 144.7 (C-8); 144.8 (C-11); 145.4 (C-7); 164.0 (C-3)ppm. The atoms were numbered according to (Supp. Inf. S1).
60%
With acetic acid In ethanol for 18h; Heating;
In toluene Heating;
In ethanol Reflux;
In ethanol Reflux;
3.1.3. General Procedure for the Preparation of {N-(3-(tert-Butyl)-1-phenyl-1H-pyrazol-5-yl)-3-((6,7-dimethoxyquinazolin-4-yl)oxy)benzamide} Derivatives Compound 9a-c
Pivaloylacetonitrile 4.07 g (32 mmol) and Phenylhydrazine 3.51 g (32 mmol) were added to40 mL ethanol and the mixture was heated to reflux for 15 h. After the solvent was evaporated,[3-(tert-butyl)-1-phenyl-1H-pyrazol-5-amine] was obtained. 138.6 mg (1 mmol) hydroxybenzoic acid in5 mL THF was added three drops of DMF and reacted with oxalyl chloride 0.5 mL in 0 °C. After 1.5 hreaction, the reaction liquid was dissolved in THF and HCl, which was dissolved in THF solution of3-(tert-butyl)-1-phenyl-1H-pyrazol-5-amine. After 3 h, the reaction mixture was evaporated; the crudeproduct was purified by column chromatography to obtain compound 8. Compound 8 was furtherreacted with compounds 5, 6, 7 in the presence of K2CO3 to obtain the final products 9a-c.
With hydrogenchloride In water at 70℃; for 2h;
2.2. Synthesis
A sample of the 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine (1) was prepared as described in the literature [27]. To a solution of 14 concentrated hydrochloric acid (3.8mL) in 15 water (33mL), 16 phenylhydrazine (2.1220g, 19.62mmol) and 17 4,4-dimethyl-3-oxopentanenitrile (1.8502g, 14.78mmol) were added. The mixture was heated at 70°C for 1h, then concentrated hydrochloric acid (3.8mL) was added and the mixture was heated additionally for 1h. After cooling, crushed ice was added and the mixture was neutralized with concentrated ammonium hydroxide. The resulting solid was filtered under reduced pressure, washed with cold water (3×5mL) and dried at ambient temperature affording the compound 1 as a pale yellow solid.
With acetic acid for 5h; Reflux;
2. General procedure for the synthesis of substrates 1
General procedure: 2.2 1n-1r was prepared in this method. Add to a mixture of a hydrazine (3 mmol), acetylacetonitrile/benzoylacetonitrile (3.6 mmol) in AcOH (10 ml). Stir the reaction mixture under reflux for 5 hours. Then, the crude mixture was purified by a silica gel column chromatography to give the products.
With hydrogenchloride In water at 70℃; for 2h;
3.1.1. Synthesis of Aminepyrazole Derivatives
General procedure: The precursor pyrazoles (Pyr in Figure 3) were synthesized following the methodology reported in the literature [34,35]. A measure of 35.18 mmol of 4,4-dimethyl-3-oxopentanenitrile (dopn in Figure 3) and 35.18 mmol of phenylhydrazine (2-nitrophenylhydrazine, 3-nitrophenylhydrazine, 4-nitrophenylhydrazine) were mixed in an Erlenmeyer flask. Then 4 mL of concentrated hydrochloric acid and 32 mL of distilled water were added, and the resulting mixture was heated to 70 C with constant stirring. After reacting for one hour, 4 mL of concentrated hydrochloric acid was added, and the mixture was heated for an additional hour. The reaction was cooled to room temperature, then placed in an ice bath and neutralized with the careful addition of ammonium hydroxide until a precipitate formed. The solids formed were vacuum filtered and washed initially with water (5 × 50 mL) and then with hexane (2 × 50 mL).
With hydrogenchloride; In ethanol; water;Heating / reflux;
A mixture of commercially available (4-methoxyphenyl)-hydrazine (17.4 g, 0.1 mol) and commercially available pivaloylacetonitrile (13.8 g, 0.11 mol) in EtOH (500 mL) and cone. HCl (50 mL) was heated at reflux overnight. After removal of the solvent, the residue was purified by column chromatography to afford 3-t-butyl-1-(4- methoxyphenyl)-lH-pyrazol-5-amine (20 g, 82% yield).
82%
With acetic acid; In ethanol; for 3h;Reflux;
4,4-Dimethyl-3-oxo-pentanenitrile (14.28 g, 1 14 mmol) and 4- methoxyphenyl hydrazine (19.89 g, 1 14 mmol) were dissolved in a mixture of absolute ethanol (170 mL) and glacial acetic acid (5.0 mL) then heated to reflux for 3 h, before allowing to standing overnight at RT. The resulting red/brown solid was filtered off and the filtrate was then diluted with water (500 mL), and basified with 880 ammonia solution until the pH = 5. This aqueous solution was extracted into diethyl ether (3 x). The combined organics were dried (MgSO4) and evaporated in vacuo to a brown oil. Trituration (pentane) gave the title compound as a light purple/brown solid (23.07 g, 94.1 mmol, 82%). LCMS (method 1): Rt 2.87 min, m/z 246/247 [MH+].
82%
With acetic acid; In ethanol; for 3h;Reflux;
a. 5-tert-Butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-ylamine (Intermediate 13a) 4,4-Dimethyl-3-oxo-pentanenitrile (14.28 g, 114 mmol) and 4-methoxyphenyl hydrazine (19.89 g, 114 mmol) were dissolved in a mixture of absolute ethanol (170 mL) and glacial acetic acid (5.0 mL) then heated to reflux for 3 h, before allowing to standing overnight at RT. The resulting red/brown solid was filtered off, and the filtrate was then diluted with water (500 mL), and basified with 880 ammonia solution until the pH=5. This aqueous solution was extracted into diethyl ether (3*). The combined organics were dried (MgSO4) and evaporated in vacuo to a brown oil. Trituration (pentane) gave the title compound as a light purple/brown solid (23.07 g, 94.1 mmol, 82%). LCMS (method 1): Rt 2.87 min, m/z 246/247 [MH+].
With acetic acid; In ethanol; for 3h;Heating / reflux;
A. General Methods for Synthesis of Heterocyclic Amines; A1 General Procedure for the Preparation of N1-Aryl-5-aminopyrazoles; [Show Image] N1-(4-Methoxyphenyl)-5-amino-3-tert-butylpyrazole: A mixture of 4-methoxyphenylhydrazine hydrochloride (3.5 g), 4,4-dimethyl-3-oxopentanenitrile (2.5 g), EtOH (30 mL), and AcOH (1 mL) was heated at the reflux temperature for 3 h, cooled to room temp., and poured into a mixture of Et2O (100 mL) and a 10% Na2CO3 solution (100 mL). The organic layer was washed with a saturated NaCl solution, dried (MgSO4) and concentrated under reduced pressure. The solid residue was washed with pentane to afford the desired pyrazole as a pale brown solid. (4.25g): 1H-NMR (DMSO-d6) δ 1.18 (s, 9H); 3.78 (s, 3H); 5.02 (br s, 2H); 5.34 (s, 1H); 6.99 (d, J=8 Hz, 2H); 7.42 (d, J=8 Hz, 2H).
General procedure: A solution of the corresponding substituted phenylhydrazine hydrochloride (1 equiv.) and pivaloylacetonitrile (1.2 equiv.) was stirred overnight at 80 °C in ethanol. The solution was extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered, and evaporated to dryness.#10;#10;
79%
With hydrogenchloride; In ethanol; for 48h;Reflux;
General procedure: A solution of 4-tolyllhydrazine hydrochloride(5.20 g, 33 mmol) and pentylacyl acetonitrile (3.75 g, 30 mmol) in 0.4 M ethanolic solution of HCl(100 mL) was heated under reflux during 48 h. After cooling to room temperature, 1M NaOH wasadded to the mixture until the pH reached 10?11. The mixture was partitioned between water and ethylacetate. The water phase was extracted twice with dichloromethane. The organic phases werecombined and washed with water and brine, then dried with Na2SO4. Evaporation of the solvent invacuo afforded the crude product, which was subjected to recrystallization from ethyl acetate andpetroleum ether to produce compound 25a as a white solid (5.88 g, 86percent yield).
With acetic acid; In ethanol;Reflux;
General procedure: A solution of pivoloylacetonitrile 4 (1.0 g, 8.0 mmol). substituted phenylhydrazine hydrochlorides (0.83 mL, 8.39 mmol) and a few drops of glacial acetic acid in ethanol were refluxed in absolute alcohol overnight. The solvent was evaporated by vacuum distillation and the residue was washed with petroleum ether. The solid was taken in ethyl acetate and washed with aqueous NaHCO3. The organic layer was further washed with brine, water and evaporated to yield the desired product as a crystalline solid in 80-90percent yield (~ 89percent )24.
Step C: 5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylamine A solution of p-tolyl-hydrazine hydrochloride (15.86 g, 100 mmol) and pivaloylacetonitrile (17.9 g, 143 mmol) dissolved in MeOH (65 mL) was heated to reflux for 18 hours under N2 atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated with ether and collected by filtration. The solid was dried under high vacuum to provide 26.6 g of white solid (99% yield).
86%
With hydrogenchloride; In ethanol; for 48h;Reflux;
A solution of 4-tolyllhydrazine hydrochloride(5.20 g, 33 mmol) and pentylacyl acetonitrile (3.75 g, 30 mmol) in 0.4 M ethanolic solution of HCl(100 mL) was heated under reflux during 48 h. After cooling to room temperature, 1M NaOH wasadded to the mixture until the pH reached 10-11. The mixture was partitioned between water and ethylacetate. The water phase was extracted twice with dichloromethane. The organic phases werecombined and washed with water and brine, then dried with Na2SO4. Evaporation of the solvent invacuo afforded the crude product, which was subjected to recrystallization from ethyl acetate andpetroleum ether to produce compound 25a as a white solid (5.88 g, 86% yield).
86.4%
With hydrogenchloride; In ethanol; at 80℃; for 8h;
A solution of 4-tolyllhydrazine hydrochloride (5.20 g,33 mmol) and pentylacyl acetonitrile (3.75 g, 30 mmol) in 0.4 M ethanolic solution of HCl (100 mL)was heated under reflux during 8 h. After cooling to room temperature, 1 M NaOH was added to the mixture until the pH reached 10-11. The mixture was partitioned between water and ethyl acetate. The water phase was extracted twice with dichloromethane. The organic phases were combined and washed with water and brine, then dried with Na2SO4. Evaporation of the solvent in vacuo afforded the crude product, which was subjected to recrystallization from ethyl acetate and petroleum ether to produce compound 2a as a white solid (5.88 g,). Yield: 86.4%. 1H-NMR (CDCl3, 400 MHz), delta: 7.40 (d, 2H),7.25 (d, 2H), 5.50 (s, 1H), 4.72 (brs, 2H), 2.37 (s, 3H), 1.32 (s, 9H). ESI-MS (+Q, m/z): 230 [M + H]+,252 [M + Na]+.
52%
With hydrogenchloride; In ethanol; water;Reflux;
Intermediate A: 3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-amine To a stirred solution of p-tolylhydrazine hydrochloride (100 g, 630 mmol) in EtOH (1251 mL) was added 4,4-dimethyl-3-oxopentanenitrile (88 g, 699 mmol) and HCl (62.5 mL, 750 mmol). The resulting mixture was stirred at reflux overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo to c.a. 1/3 of the original volume. The reaction mixture was then cooled in an ice-bath and taken to c.a. pH 8-9 with 6M aq NaOH. The reaction mixture was extracted with diethyl ether (500 mL) and the organic phase washed with water (2*300 mL) before being dried over magnesium sulphate and concentrated in vacuo to afford an orange solid. The solid was suspended in iso-hexane and stirred at reflux for 2.5 h before being cooled and filtered whilst still hot to yield the subtitle product 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine as a pale brown solid (76.5 g, 52%); Rt 1.31 min (Method 1); m/z 230 (M+H)+ (ES+); 1H NMR delta: 1.20 (9H, s), 2.32 (3H, s), 5.10 (2H, br s), 5.35 (1H, s), 7.24 (2H, d), 7.42 (2H, m).
In ethyl acetate; N,N-dimethyl-formamide; toluene;Heating / reflux;
1.4 Preparation of 5-tert-butyl-2p-tolyl-2H-pyrazol-3-ylamine ("1d") 5 g of p-tolylhydrazine hydrochloride and 3.8 g of 4,4-dimethyl-3-oxopentanenitrile are dissolved in 100 ml of toluene. The entire mixture is refluxed overnight. For work-up, the solvent is stripped off in a rotary evaporator. Water is added to the residue, which is then extracted with ethyl acetate. The organic phase is dried using Na2SO4, filtered. The filtrate is evaporated in a rotary evaporator and chromatographed (petroleum ether/ethyl acetate 1/1), giving 5.7 g of "1d", HPLC/MS [M+H+] 230.
30 g
In ethanol; for 1.5h;
Pivaloylacetonitrile (19.0 g) was refluxed with tolylhydrazine hydrochloride (24.0 g) in ethanol (190 ml) for 1.5 hr. The solution was cooled and volatiles removed in vacuo. The residue was extracted with ethyl acetate and 10% aq. sodium carbonate, and the organic layer washed with water and brine. Drying over sodium sulfate and solvent removal afforded pyrazole 6 as an off-white solid (30 g).
In ethanol; at 80℃;
General procedure: A solution of the corresponding substituted phenylhydrazine hydrochloride (1 equiv.) and pivaloylacetonitrile (1.2 equiv.) was stirred overnight at 80 C in ethanol. The solution was extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered, and evaporated to dryness. 3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-amine (2a). From p-tolylhydrazine hydrochloride (1.59 g, 10 mmol)and pivaloylacetonitrile (1.5 g, 12 mmol), after work-up and without further purification, compound 2a was obtained as a white solid (1.8 g, 80%). IR (KBr): 3345, 1598, 1578 cm-1; 1H-NMR (CDCl3) delta: 7.40 (d, 2H, J = 8.8 Hz), 7.25 (d, 2H, J = 8.8 Hz), 5.50 (s, 1H), 3.72 (brs, 2H, NH2), 2.37 (s, 3H), 1.32 (s,9H). MS (ESI): m/z 252.16 [M + Na]+. Mp 121.3-123.4 C.
3.6 g
In ethanol; for 1.5h;Reflux;
Pivaloylacetonitrile (1 ) (1.9 g, 15.1 mMol) was placed in a flask with tolylhydrazine hydrochloride (2.4 g, 15.1 mMol) in ethanol (19 mL) and the solution was heated to reflux for 1.5 hr. The solution was concentrated in vacuo until only a small amount of ethanol remained whereupon it was triturated with hexane, allowing it to stir for 1 hr before filtration of the white solid. Pyrazole 2 was isolated as its hydrochloride salt (3.6 g. 1.35 mMol) and was determined to be pure by LC-MS analysis (M+H=230.1).
4,4-Dimethyl-3-oxopentanenitrile (36.7 g, 0.29 mol), <strong>[635-26-7](2-methylphenyl)hydrazine hydrochloride</strong> (47.7 g, 0.29 mol), and glacial acetic acid (7.03 g, 6.7 mL, 0.12 mol) were dissolved in abs ethanol (585 mL) and heated under reflux for 18 h. After removal of the solvent under reduced pressure, EtOAc and water (500 mL each) were added, then sodium bicarbonate (42 g, 0.50 mol) was carefully added. After addition of hexane (500 mL), the organic phase was separated, washed with brine (500 mL), and dried over Na2SO4. The mixture was then filtered through a pad of silica gel (500 g) on a sintered glass funnel. The pad was eluted with hexanes/EtOAc (1:1, v/v), and the filtrate was concentrated under reduced pressure. The resulting solid was triturated with hexanes/EtOAc (9:1, v/v), filtered, washed and dried in vacuo to afford the product as a colorless solid (61.5 g, 93%). 1H NMR (400 MHz, CD2Cl2) 61.29 (s, 9H), 2.12 (s, 3H), 3.56 (br, 2H), 5.48 (s, 1H), 7.28 (m, 2H), 7.31 (m, 2H).
93%
4, 4-Dimethyl-3-oxopentanenitrile (36.7 g, 0.29 mol), (2-methylphenyl) hydrazine hydrochloride (47.7 g, 0.29 mol), and glacial acetic acid (7.03 g, 6.7 mL, 0.12 mol) were dissolved in abs ethanol (585 mL) and heated under reflux for 18 h. After removal of the solvent under reduced pressure, EtOAc and water (500 mL each) were added, then sodium bicarbonate (42 g, 0.50 mol) was carefully added. After addition of hexane (500 mL), the organic phase was separated, washed with brine (500 mL), and dried over Na2S04. The mixture was then filtered through a pad of silica gel (500 g) on a sintered glass funnel. The pad was eluted with hexanes/EtOAc (1: 1, v/v), and the filtrate was concentrated under reduced pressure. The resulting solid was triturated with hexanes/EtOAc (9: 1, v/v), filtered, washed and dried in vacuo to afford a colorless solid (61.5 g, 93 %).'H NMR (400 MHz, CD2CI2) 8 1.29 (s, 9H), 2.12 (s, 3H), 3.56 (br, 2H), 5.48 (s, 1H), 7.28 (m, 2H), 7.31 (m, 2H).
With triethylamine; In toluene; at 110℃;
Step 34.1 : 5-tert-Butyl-2-o-tolyl-2H-pyrazol-3-ylamine; EPO <DP n="79"/>A solution of o-tolyl-hydrazine hydrochloride (0.3 mmol) in 0.5 mL of toluene with 4,4- dimethyl-3-oxopentanenitrile (375 mg, 3 mmol, 10 equiv) and Et3N (84 muL, 0.6 mmol, 2 equiv) is stirred at 1100C overnight. The solvent is evaporated and the residue taken up in EtOAC and washed with saturated NaHCO3 and brine. The organic layer is then concentrated and the residue diluted in 1 mL of ethanol and 1 mL of 1M HCI. The mixture was left at rt for 15 min and then it was concentrated. 5-tert-Butyl-2-o-tolyl-2H-pyrazol-3- ylamine is used crude in the preparation of Example 34.
With hydrazine hydrate In methanol at 120℃; for 0.666667h; microwave irradiation;
97%
With hydrazine hydrate In ethanol at 110℃; for 7h; Inert atmosphere;
A solution of 4,4-dimethyl-3-oxopentaneϖitriIe (Compound [CCLII]) (7 g, 55.9 mmol, 1.00 equiv) and NH2NH2-H2O (4.5 g, 140 mmol, 2.00 equiv) in EtOH (100 mL) was stirred for 7 h at HO°C under nitrogen. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether =1:2). After cooling, the resulting solution was concentrated under vacuum and diluted with 50 mL of water. The resulting solution was extracted with CH2Cl2, dried and concentrated under reduced pressure. The residue was loaded onto a silica gel column with ethyl acetate/petroleum ether as the eluent to Compound [CCXXXTV] as a yellowish oil: LCMS (m/e) 140 (M+H); 1HNMR (300 MHz, DMSO-d6) δ ppm 5.18 (s, 1 H), 1.19 (s, 9H). Amount obtained: 7.6 g, 97% yield.
89%
With hydrazine hydrate In ethanol for 3h; Reflux;
1.j03
At room temperature 4,4-dimethyl-3-oxopentanenitrile (J-Il) (1 eq., 5 g) was taken up in EtOH (100 ml), mixed with hydrazine hydrate (2 eq., 4.42 g) and refluxed for 3 h. The residue obtained after removal of the EtOH by distillation was taken up in water (100 ml) and extracted with EE (300 ml). The combined organic phases were dried over sodium sulphate, the solvent was removed under vacuum and the product (J-III) (5 g, 89 % yield) was obtained as a light red solid after recrystallisation from hexane (200 ml).
89%
With hydrazine hydrate In ethanol for 3h; Reflux;
1.j03
At room temperature 4,4-dimethyl-3-oxopentanenitrile (J-Il) (1 eq., 5 g) was taken up in EtOH (100 ml), mixed with hydrazine hydrate (2 eq., 4.42 g) and refluxed for 3 h. The residue obtained after removal of the EtOH by distillation was taken up in water (100 ml) and extracted with EE (300 ml). The combined organic phases were dried over sodium sulphate, the solvent was removed under vacuum and the product (J-III) (5 g, 89 % yield) was obtained as a light red solid after recrystallisation from hexane (200 ml).
89%
With hydrazine hydrate In ethanol for 3h; Reflux;
1.j03
4,4-dimethyl-3-oxopentane nitrile (J-II) (1 equiv., 5 g) was taken up at room temperature in EtOH (100 mL), hydrazine hydrate (2 equiv., 4.42 g) was added, and the mixture was refluxed for 3 h. The residue obtained after distilling off the EtOH was taken up in water (100 mL) and extracted with EE (300 mL). The combined organic phases were dried over sodium sulphate, the solvent was removed in vacuo and the product (JAI) (5 g, 89% yield) was obtained as a pale red solid after recrystallisation from hexane (200 mL).
89%
With hydrazine hydrate In ethanol for 3h; Reflux;
1.j03
Step j03: At room temperature 4,4-dimethyl-3-oxopentanenitrile (J-II) (1 eq., 5 g) was taken up in EtOH (100 ml), mixed with hydrazine hydrate (2 eq., 4.42 g) and refluxed for 3 h. The residue obtained after removal of the EtOH by distillation was taken up in water (100 ml) and extracted with EE (300 ml). The combined organic phases were dried over sodium sulphate, the solvent was removed under vacuum and the product (J-III) (5 g, 89% yield) was obtained as a light red solid after recrystallisation from hexane (200 ml).
89%
With hydrazine hydrate In ethanol for 3h; Reflux;
1.j03
At room temperature 4,4-dimethyl-3-oxopentanenitrile (J-ll) (1 eq., 5 g) was taken up in EtOH (100 ml), mixed with hydrazine hydrate (2 eq., 4.42 g) and refluxed for 3 h. The residue obtained after removal of the EtOH by distillation was taken up in water (100 ml) and extracted with EE (300 ml). The combined organic phases were dried over sodium sulphate, the solvent was removed under vacuum and the product (J-lll) (5 g, 89 % yield) was obtained as a light red solid after recrystallisation from hexane (200 ml).
89%
With hydrazine hydrate In ethanol for 3h; Reflux;
1.j03
Step j03: At room temperature 4,4-dimethyl-3-oxopentanenitrile (J-II) (1 eq., 5 g) was taken up in EtOH (100 ml), mixed with hydrazine hydrate (2 eq., 4.42 g) and refluxed for 3 h. The residue obtained after removal of the EtOH by distillation was taken up in water (100 ml) and extracted with EE (300 ml). The combined organic phases were dried over sodium sulfate, the solvent was removed under vacuum and the product (J-III) (5 g, 89% yield) was obtained as a light red solid after recrystallisation from hexane (200 ml).
89%
With hydrazine hydrate In ethanol for 3h; Reflux;
1.j03 Step j03:
At room temperature 4,4-dimethyl-3-oxopentanenitrile (J-ll) (1 equivalents, 5 g) was taken up in ethanol (100 mL), mixed with hydrazine hydrate (2 equivalents, 4.42 g) and refluxed for 3 h. The residue obtained after removal of the ethanol by distillation was taken up in water (100 mL) and extracted with ethyl acetate (300 mL). The combined organic phases were dried over sodium sulphate, the solvent was removed under vacuum and the product (J-lll) (5 g, 89 % yield) was obtained as a light red solid after recrystallisation from n- hexane (200 mL).
89%
With hydrazine hydrate In ethanol for 3h; Reflux;
j03
Step j03:[0668]At room temperature 4,4-dimethyl-3-oxopentanenitrile (J-II) (1 equivalents, 5 g) was taken up in ethanol (100 mL), mixed with hydrazine hydrate (2 equivalents, 4.42 g) and refluxed for 3 h. The residue obtained after removal of the ethanol by distillation was taken up in water (100 mL) and extracted with ethyl acetate (300 mL). The combined organic phases were dried over sodium sulfate, the solvent was removed under vacuum and the product (JAI) (5 g, 89% yield) was obtained as a light red solid after recrystallisation from n-hexane (200 mL).
89%
With hydrazine hydrate In ethanol at 20℃; for 3h; Reflux;
j.03 1. Synthesis of (3-tert-butyl-1 -(3-chlorophenyl)-1 H-pyrazol-5-yl)methanamine (steps i01 -i06) Step j03:
At room temperature 4,4-dimethyl-3-oxopentanenitrile (J-ll) (1 equivalents, 5 g) was taken up in ethanol (100 mL), mixed with hydrazine hydrate (2 equivalents, 4.42 g) and refluxed for 3 h. The residue obtained after removal of the ethanol by distillation was taken up in water (100 mL) and extracted with ethyl acetate (300 mL). The combined organic phases were dried over sodium sulphate, the solvent was removed under vacuum and the product (J-ll I ) (5 g, 89 % yield) was obtained as a light red solid after recrystallisation from n- hexane (200 mL).
89%
With hydrazine hydrate In ethanol for 3h; Reflux;
1.j03
Step j03: At room temperature 4,4-dimethyl-3-oxopentanenitrile (J-ll) (1 equivalents, 5 g) was taken up in ethanol (100 mL), mixed with hydrazine hydrate (2 equivalents, 4.42 g) and refluxed for 3 h. The residue obtained after removal of the ethanol by distillation was taken up in water (100 mL) and extracted with ethyl acetate (300 mL). The combined organic phases were dried over sodium sulphate, the solvent was removed under vacuum and the product (J-ll I ) (5 g, 89 % yield) was obtained as a light red solid after recrystallisation from n-hexane (200 mL).
89%
With hydrazine hydrate In ethanol for 3h; Reflux;
1.j03
Step j03: At room temperature 4,4-dimethyl-3-oxopentanenitrile (J-ll) (1 equivalents, 5 g) was taken up in ethanol (100 mL), mixed with hydrazine hydrate (2 equivalents, 4.42 g) and refluxed for 3 h. The residue obtained after removal of the ethanol by distillation was taken up in water (100 mL) and extracted with ethyl acetate (300 mL). The combined organic phases were dried over sodium sulphate, the solvent was removed under vacuum and the product (J-III) (5 g, 89 % yield) was obtained as a light red solid after recrystallisation from n- hexane (200 mL).
89%
With hydrazine hydrate In ethanol for 3h; Reflux;
1.j03
Step j03: At room temperature 4,4-dimethyl-3-oxopentanenitrile (J-II) (1 equivalents, 5 g) was taken up in ethanol (100 mL), mixed with hydrazine hydrate (2 equivalents, 4.42 g) and refluxed for 3 h. The residue obtained after removal of the ethanol by distillation was taken up in water (100 mL) and extracted with ethyl acetate (300 mL). The combined organic phases were dried over sodium sulphate, the solvent was removed under vacuum and the product (J-III) (5 g, 89 % yield) was obtained as a light red solid after recrystallisation from n-hexane (200 mL).
77%
With hydrazine hydrate In methanol at 150℃; for 0.0833333h; Microwave irradiation;
1.2. General procedure of microwave synthesis of pyrazoles
General procedure: A microwave tube was charged with ketonitrile (2.0 mmol), methanol (1 mL), and hydrazine monohydrate (2.6 mmol) and subjected to microwave irradiation (100 W, 150 °C) for 5 minutes. Volatiles were subsequently removed under reduced pressure. The residue was purified by either trituration with cold methanol or cyclohexane, or by using column chromatography to give the final product.
77%
With hydrazine hydrate In methanol at 150℃; for 0.0833333h; Microwave irradiation;
1.2 General procedure for the microwavesynthesis of pyrazoles
General procedure: Amicrowave tube was charged with ketonitrile (2.0 mmol), methanol (1 mL), andhydrazine monohydrate (2.6 mmol) and subjected to microwave irradiation (100 W,150 °C) for 5 minutes.1 Volatiles were subsequently removed underreduced pressure. The residue was purified by either trituration with coldmethanol or cyclohexane, or by using column chromatography to give the finalproduct.
74%
With hydrazine hydrate In ethanol for 1h; Heating;
With hydrazine In toluene Heating;
With hydrazine hydrate Neat (no solvent); Heating;
With hydrazine hydrate In ethanol for 3h; Reflux;
1.j03
Step j03: At room temperature 4,4-dimethyl-3-oxopentanenitrile (J-ll) (1 eq., 5 g) was taken up in EtOH (100 ml), mixed with hydrazine hydrate (2 eq., 4.42 g) and refluxed for 3 h. The residue obtained after removal of the EtOH by distillation was taken up in water (100 ml) and extracted with EE (300 ml). The combined organic phases were dried over sodium sulphate, the solvent was removed under vacuum and the product (J-lll) (5 g, 89 % yield) was obtained as a light red solid after recrystallisation from hexane (200 ml).
With hydrazine hydrate In methanol at 140℃; for 1h; Microwave irradiation;
General procedure: Initially, cyanoacetophenones (6) were accomplished through the reaction of substituted bromoacetophenones (5) (10 mmol)with sodium cyanide (20 mmol). 5-aminopyrazoles (7) were then prepared from the cyclocondensation of cyanoacetophenones (6)(10 mmol) with hydrazine (20 mmol) under microwave irradiation [26,27]. Moreover, 3,5-diaminopyrazoles (11) were synthesized via an initial formation of mono-substituted malononitriles (10) from the condensation of substituted aromatic or heteroaromatic aldehydes (9) (10 mmol) with malononitrile (10 mmol), as described previously [28]. The resulting mono-substituted malononitriles (10) (10 mmol) were subsequently treated with hydrazinehydrate (20 mmol) in refluxing ethanol to obtain 3,5-diaminopyrazoles (11). In the next step, the reactions between 5-aminopyrazoles (7)/3,5-diaminopyrazoles (11) (3 mmol) and ethoxycarbonyl isothiocyanate (3.3 mmol) in anhydrous DMF (4 mL) at room temperature yielded corresponding thiourea (8 and 12) derivatives. To a stirred solution of sodium hydroxide (9 mmol) in ethanol (80%, 20 mL), carbethoxythiourea derivatives (8 and 12) (3 mmol) were added and heated on a water bath for 20 min. After cooling, the solvent was slowly evaporated under vacuum, and the residue was suspended in water (25 mL). The resulting suspension was then acidified up to pH 1-3 using 2.5 M HCl. The precipitated products (3-3c and 4-4n) was filtered off, purified with an appropriate solvent, and dried under vacuum (Schemes 1 and 2).
With hydrazine hydro-chloride In ethanol; water Reflux;
2-(2,2-dimethyl-propionyl)-tridecanenitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With carbonyl(dihydrido)tris(triphenylphosphine)ruthenium(II); piperdinium acetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene for 4h; Heating;
85%
With carbonyl bis(hydrido)tris(triphenylphosphine)ruthenium(II); piperdinium acetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 110℃; for 3h; Inert atmosphere;
85%
With carbonyl(dihydrido)tris(triphenylphosphine)ruthenium(II); piperdinium acetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene for 4h; Reflux;
With acetic acid; In tetrahydrofuran; ethanol; for 16h;Heating / reflux;
A mixture of 4,4-dimethyl-3-oxo-pentanenitrile (4.52 g, 36.15 mmol), 4- hydrazinobenzoic acid (5.00 g, 32.86 mmol), and acetic acid (2 mL) in EtOH/THF (1:1) was refluxed for 16 h. After cooling, the solvent was concentrated under reduced pressure, and the crude was re-dissolved in EtOAc. The organic layer was <n="77"/>washed successively with saturated aqueous solution of Na2Ctheta3 and brine, dried (MgSO4), filtered, and concentrated under reduced pressure to half its volume. The resulting precipitate was filtered, and the solids were washed with cold EtOAc and dried under high vacuum to afford the title compound as a white solid (8.4 g, 99%). 1H-NMR (DMSO-cfe) delta 12.91 (s, 1 H), 7.99 (d, J = 6.0 Hz, 2H), 7.75 (d, J = 9.0 Hz, 2H), 5.42 (s, 1 H), 5.39 (s, 2H)1 1.21 (s, 9H); LC-MS m/z [M+H]+ = 260, RT = 1.83 min.
99%
With acetic acid; In tetrahydrofuran; ethanol; for 16h;Heating / reflux;
A mixture of 4,4-dimethyl-3-oxo-pentanenitrile (4.52 g, 36.15 mmol), 4- hydrazinobenzoic acid (5.00 g, 32.86 mmol), and acetic acid (2 mL) in EtOH/THF (1:1) was refluxed for 16 h. After cooling, the solvent was concentrated at reduced pressure, and the crude was re-dissolved in EtOAc. The organic layer was washed with aqueous saturated Na2C03 solution and brine, dried over MgS04, filtered, and concentrated to half its volume. The resulting residue was filtered, and the solids were washed with cold EtOAc and dried under high vacuum to afford the title compound as a white solid (8.4 g, 99%). (at)H-NMR (DMSO-d6) 8 12.91 (s, 1H), 7.99 (d, J = 6.0 Hz, 2H), 7.75 (d, J = 9.0 Hz, 2H), 5.42 (s, 1 H), 5.39 (s, 2H), 1.21 (s, 9H) ; MS LC-MS [M+H]+ = 260, RT = 1.83 min.
In toluene; at 20℃; for 12h;Heating / reflux;
Step 45.1: 4-(5-Amino-3-ferf-butyl-pyrazol-1-yl)-benzoic acid; To a suspension of 2.4 g (16 mmol) 4-hydrazino-benzoic acid in 12 mL toluene, 2.0 g of pivaloyl acetonitrile are added at rt. The suspension is heated to and kept under reflux for 12 h. After completion, the resulting reaction mixture is allowed to cool to rt. The precipitated product is isolated by filtration, washed with cold toluene and dried under high vacuum. [M+1]+= 260.
In toluene; at 20℃; for 12h;Heating / reflux;
To a suspension of 2.4 g (16 mMol) 4-hydrazino-benzoic acid in 12 mL toluene, 2.0 g of pivaloyl acetonitrile are added at rt. The suspension is heated to and kept under reflux for 12 h. After completion, the resulting reaction mixture is allowed to cool to rt. The precipitated product is isolated by filtration, washed with cold toluene and dried under high vacuum. [M+1]+=260.
Z Example Z
Example Z A mixture of Example Y (13 g, 53.3 mmol) and 4,4-dimethyl-3-oxopentanenitrile (6.9 g, 55 mol) in ethanol (150 mL) was heated to reflux overnight. The reaction solution was evaporated under reduced pressure. The residue was purified by column chromatography to give 3-[3-(5-amino-3-t-butyl-pyrazol-1-yl)-phenyl]-propionic acid ethyl ester (14.3 g, 45.4 mmol) as a white solid. 1H NMR (DMSO-d6): 7.39-7.32 (m, 3H), 7.11 (d, J=6.8 Hz, 1H), 5.34 (s, 1H), 5.16 (s, 2H), 4.03 (q, J=7.2 Hz, 2H), 2.88 (t, J=7.6 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 1.19 (s, 9H), 1.15 (t, J=7.2 Hz, 3H).
A mixture of <strong>[87565-98-8]3-hydrazino-benzoic acid hydrochloride</strong> (200 g, 1.06 mol) and 4,4-dimethyl-3-oxo-pentanenitrile (146 g, 1.167 mol) in ethanol (2 L) was heated to reflux overnight. The reaction solution was evaporated under reduced pressure. The residue was purified by column chromatography to give 3-(5-amino-3-t-butyl-pyrazol-1-yl)-benzoic acid ethyl ester (116 g, 40%) as a white solid together with 3-(5-amino-3-t-butyl-pyrazol-1-yl)-benzoic acid (93 g, 36%).
With hydrogenchloride; sodium hydroxide; hydroxylamine sulfate; triethylamine; In methanol; toluene;
EXAMPLE 1 To a suspension of cyanopinacolone (75.102 g) in a mixture of anhydrous toluene (150 ml) and anhydrous methanol (26.7 ml) is introduced gaseous hydrogen chloride (26.3 g) with cooling at 5 to 10 C. and stirring, and the whole mixture is allowed to stand at 10 to 12 C. for 23 hours. To the reaction mixture is dropwise added anhydrous methanol (750 ml), then triethylamine (185.178 g) with cooling and stirring to make a complete solution. The reaction mixture is treated with hydroxylamine sulfate (51.704 g) and stirred at 50 C. for 2 hours. Then, conc. hydrochloric acid (112.629 g) is dropwise added to the mixture, which is stirred at 50 C. for 1 hour. After evaporating the solvent under reduced pressure from the reaction mixture, the residue is made alkaline with 48% aqueous sodium hydroxide with cooling, and the aqueous solution is shaken with toluene. The organic layer is washed with water, subjected to azeotropic distillation under atmospheric pressure, and evaporated to dryness to remove the solvent, whereby 3-amino-5-t-butylisoxazole (79.480 g) is obtained. Melting point is 106 to 109 C. Yield is 94.5%.
77%
With hydroxylamine hydrochloride; sodium hydroxide; In water; at 20℃; for 0.5h;
4,4-dimethyl-3-oxopentanenitrile (3 g, 23.97 mmol) was dissolved in distilled water, stirred, and added with NaOH (1.06 g, 26.4 mmol) and NH2OH-HCl (1.83 g, 26.4 mmol). The reaction solution was stirred for about 30 minutes at room temperature. The reaction mixture was calibrated to yield pH in a range of 8 to 9 by adding an aqueous solution of 1 N NaOH, followed by further stirring for 10 hours or more at 50C. The reaction mixture was washed 2 to 3 times with carbon tetrachloride, and aqueous layer was calibrated to yield pH in a range of 4 to 5 by adding concentrated HC1. The reaction mixture was further stirred for about 3 hours at 50C. The reaction mixture was cooled to room temperature, and calibrated to yield pH 12 by adding an aqueous solution of 1 N NaOH. The resulting solid was filtered under reduced pressure, and washed with distilled water. The filtered solid was dried with warm wind in an oven (40C) for 3 hours or more to obtain the title compound (2.6 g, 77%). -NMR Spectrum (300 MHz, DMSO-i: delta 5.49 (s, 1H), 5.40 (s, 2H), 1.21 (s, 9H) MS(ESI+, m/z): 141 [M+H]+
77%
4,4-dimethyl-3-oxopentanenitrile (3 g, 23.97 mmol) was dissolved in distilled water, stirred, and added with NaOH (1.06 g, 26.4 mmol) and NH2OH.HCl (1.83 g, 26.4 mmol). The reaction solution was stirred for about 30 minutes at room temperature. The reaction mixture was calibrated to yield pH in a range of 8 to 9 by adding an aqueous solution of 1 N NaOH, followed by further stirring for 10 hours or more at 50 C. The reaction mixture was washed 2 to 3 times with carbon tetrachloride, and aqueous layer was calibrated to yield pH in a range of 4 to 5 by adding concentrated HCl. The reaction mixture was further stirred for about 3 hours at 50 C. The reaction mixture was cooled to room temperature, and calibrated to yield pH 12 by adding an aqueous solution of 1 N NaOH. The resulting solid was filtered under reduced pressure, and washed with distilled water. The filtered solid was dried with warm wind in an oven (40 C.) for 3 hours or more to obtain the title compound (2.6 g, 77%). 1H-NMR Spectrum (300 MHz, DMSO-d6): delta 5.49 (s, 1H), 5.40 (s, 2H), 1.21 (s, 9H) MS (ESI+, m/z): 141 [M+H]+
70%
With hydroxylamine hydrochloride; sodium hydroxide; In water; at 25℃; for 0.5h;
To a solution of pivaloylacetonitrile (3 g, 23.97 mmol) in water (20 mL), NaOH (1.06 g, 26.4 mmol) and hydroxylamine hydrochloride (1.83 g, 26.4 mmol) were added continuously with stirring. The resulting solution was stirred for approximately 30 min at room temperature, and the pH adjusted to 10-11 with 1 M NaOH. After stirring for 10 h or more at 50 C, the mixture was cooled and washed two to three times with carbon tetrachloride. The aqueous layer was acidified with concentrated HC1 until the pH = 4-5, and then further stirred for approximately 3 h at 50 C. The reaction mixture was cooled to room temperature, and adjusted to pH 12 by adding an aqueous solution of 1 N NaOH. The resulting solid was filtered, washed with distilled water, and driedin air to obtain compound 25s as a white solid (2.0 g, yield: 70%).
84.74%.
With hydrogenchloride; sodium hydroxide; hydroxylamine hydrochloride; In ethanol;
EXAMPLE 1 In a mixture of pivaloylacetonitrile (25.03 g) and 50% (v/v) ethanol (400 ml) is dissolved 96% sodium hydroxide (9.583 g). To this solution is added hydroxylamine hydrochloride (purity, 96%) at 27 C. to give a solution (pH 7.8), which is stirred at 60 C. for 22 hours. The reaction mixture is cooled at 20 C., mixed with conc. hydrochloric acid (9.11 g), and stirred at 50 C. for 2 hours. Conc. hydrochloric acid (14.18 g) is added to the mixture, which is refluxed at 100 C. for 1 hour. The reaction mixture is concentrated under reduced pressure to remove ethanol and the residue is mixed with 30% sodium hydroxide (62 g). The mixture is shaken with chloroform. The chloroform layer is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3-amino-5-t-butylisoxazole (23.76 g). Yield, 84.74%. m.p. 101-109.5 C. Purity, 95.1%.
With hydroxylamine hydrochloride; In ethanol; hexane; water;
EXAMPLE 1 7-(1,1-dimethylethyl)-3-methyl-2H-isoxazolo-[2,3a]-(1,3,5)-triazine-2,4(3H)-dione hydrochloride (1) A solution of 41.5 g of hydroxylamine hydrochloride in 136 ml of water was added drop-by-drop over a 10-minute period to a stirred, refluxing mixture of 56.1 g of pivaloylacetonitrile (British Pat. No. 2,014,992), 700 ml of water and 525 ml of ethanol. The mixture was held under those conditions for 7 hours, the pH of the mixture being periodically adjusted to 6.5 by the addition of either hydrogen chloride or aqueous sodium hydroxide solution, as required. Then the solvent ethanol was evaporated in a rotary evaporator, and the residual liquid was dried (MgSO4), dissolved in 200 ml of hexane and chilled. Filtration gave 3-amino-5-(1,1-dimethylethyl)-isoxazole (1A), a yellow solid, m.p.: 107-109 C.
A3. General Method for the Preparation of 5-Amino-1-alkyl-3-alkylpyrazoles; 5-Amino-3-tert-butyl-1-(2-cyanoethyl)pyrazole; A solution of 4,4-dimethyl-3-oxopentanenitrile (5.6 g, 44.3 mmol) and 2-cyanoethyl hydrazine (4.61 g, 48.9 mmol) in EtOH (100 mL) was heated at the reflux temperature overnight after which TLC analysis showed incomplete reaction. The mixture was concentrated under reduced pressure and the residue was filtered through a pad of silica (gradient from 40% EtOAc/60% hexane to 70% EtOAc/30% hexane) and the resulting material was triturated (Et2O/hexane) to afford the desired product (2.5 g, 30%): TLC (30% EtOAc/70% hexane) Rf 0.31; 1H-NMR (DMSO-d6) delta 1.13 (s, 9H), 2.82 (t, J=6.9 Hz, 2H), 4.04 (t, J=6.9 Hz, 2H), 5.12 (br s, 2H), 5.13 (s, 1H).
30%
In ethanol;Reflux;
A3. General Method for the Preparation of 5-Amino-1-alkyl-3-alkylpyrazoles 5-Amino-3-tert-butyl-1-(2-cyanoethyl)pyrazole: A solution of 4,4-dimethyl-3-oxopentanenitrile (5.6 g, 44.3 mmol) and 2-cyanoethyl hydrazine (4.61 g, 48.9 mmol) in EtOH (100 mL) was heated at the reflux temperature overnight after which TLC analysis showed incomplete reaction. The mixture was concentrated under reduced pressure and the residue was filtered through a pad of silica (gradient from 40% EtOAc/60% hexane to 70% EtOAc/30% hexane) and the resulting material was triturated (Et2O/hexane) to afford the desired product (2.5 g, 30%): TLC (30% EtOAc/70% hexane) Rf 0.31; 1H-NMR (DMSO-d6) delta 1.13 (s, 9H), 2.82 (t, J=6.9 Hz, 2H), 4.04 (t, J=6.9 Hz, 2H), 5.12 (br s, 2H), 5.13 (s, 1H).
30%
In ethanol;Heating / reflux;
5-Amino-3-tert-butyl-1-(2-cyanoethyl)pyrazole: A solution of 4,4-dimethyl-3-oxopentanenitrile (5.6 g, 44.3 mmol) and 2-cyanoethyl hydrazine (4.61 g, 48.9 mmol) in EtOH (100 mL) was heated at the reflux temperature overnight after which TLC analysis showed incomplete reaction. The mixture was concentrated under reduced pressure and the residue was filtered through a pad of silica (gradient from 40% EtOAc/60% hexane to 70% EtOAc/30% hexane) and the resulting material was triturated (Et2O/hexane) to afford the desired product (2.5 g, 30%): TLC (30% EtOAc/70% hexane) Rf 0.31; 1H-NMR (DMSO-d6) delta 1.13 (s, 9H), 2.82 (t, J=6.9 Hz, 2H), 4.04 (t, J=6.9 Hz, 2H), 5.12 (br s, 2H), 5.13 (s, 1H).
35; I
EXAMPLE 35 General Synthetic Procedure I Preparation of 5-tert-Butvl-2- (6-chloro-pyrazin-2-)-2H-pyrazol-3-ylamine A mixture of 2-chloro-6-hydrazinopyrazine (65 mg, 0.45 mmol) and pivaloylacetonitrile (57,0. 45 mmol, 1 eq) in EtOH (2 ml) were refluxed for 16 hours. The reaction was evaporated to dryness in vacuo and partitioned between water and EtOAc. The organic layer was separated and dried with brine and then over MgS04. The product was filtered, evaporated to dryness and purified by column chromatography to yield the product. LCMS 4.57 min, m/z [M+H] + 252.
5-tert-butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-ylamine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
In toluene; for 5h;Heating / reflux;
To a solution of commercially available <strong>[39232-91-2]3-methoxyphenylhydrazine hydrochloride</strong> (1.0 g, 5.7 mmol) in toluene (5 mL) was added commercially available pivaloylacetonitrile (0.70 g, 5.5 mmol). The reaction mixture was heated at reflux for 5h, filtered and washed with hexane to obtain 3-t-butyl- 1-(3-methoxyphenyl)-lH-pyrazol-5-amine (1.22 g, 89% yield) as its hydrochloride salt as a pale yellow solid which was used without further purification.
56%
To a solution of 4,4-dimethyl-3-oxo-pentanenitrile (5.0 g, 40 mmol) and 3-methoxy- phenylhydrazine hydrochloride (7.0 g, 40 mmol) in anhydrous ethanol (200 ml_) was added acetic acid (1.2 mL). The reaction mixture was heated at reflux overnight, then cooled to room temperature and concentrated under reduced pressure. The residue was combined with ethyl acetate (200 mL), and washed with saturated aq NaHCO3, water, and brine. The solution was dried (Na2SO4), filtered and concentrated evaporated under reduced pressure. The residue was re-dissolved in ethanol (100 mL). A solution of 2M HCI in ether was added and the mixture was stirred for 30 min. The solvent was removed at reduced pressure, the solid residue was triturated and washed with hexane (50 mL) and then dried in a vacuum oven overnight to give the product 5-teAf-butyl-2-(3-methoxy-phenyl)~2H-pyrazol-3-ylamine hydrochloride (5.46 g, 56%) as a solid. 1H-NMR (DMSO-Cf6) delta 7.50 (t, 1 H)1 7.10 (m, 3H), 5.60 (s, 1H), 3.80 (s, 3H), 1.30 (s, 9H); LC-MS m/z [M+H]+ = 246.2, RT = 1.90 min.
56%
To a solution of 4,4-dimethyl-3-oxo-pentanenitrile (5.0 g, 40 mmol) and 3- methoxy-phenylhydrazine hydrochloride (7.0 g, 40 mmol) in anhydrous ethanol (200 mL) was added acetic acid (1.2 mL). The reaction mixture was heated at reflux overnight, then cooled to room temperature and concentrated at reduced pressure. The residue was combined with ethyl acetate (200 mL), and washed with saturated aq NaHC03, water, and brine. The solution was dried over Na2S04, evaporated at reduced pressure and the solid residue was re-dissolved in ethanol (100 mL). A solution of 2M HCI in ether was added and the mixture was stirred for 30 min. The solvent was removed at reduced pressure, the solid residue was triturated and washed with hexane (50 mL) and then dried in a vacuum oven overnight to give the product 5-tert-butyl-2-(3- methoxy-phenyl)-2H-pyrazol-3-ylamine hydrochloride (5.46 g, 56%) as an off-white solid. (at)H-NMR (DMSO-d6) 8 7.50 (t, 1 H), 7.10 (m, 3H), 5.60 (s, 1 H), 3.80 (s, 3H), 1.30 (s, 9H) ; MS LC-MS [M+H] (at) = 246.2, RT = 1.90 min.
3.2.1. General Method for the Synthesis of 2a-2i
General procedure: A solution of the corresponding substituted phenylhydrazine hydrochloride (1 equiv.) and pivaloylacetonitrile (1.2 equiv.) was stirred overnight at 80 °C in ethanol. The solution was extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered, and evaporated to dryness.
70%
With N-ethyl-N,N-diisopropylamine In ethanol for 18h; Heating / reflux;
20 5-tert-Butyl-2-phenyl-2H-pyrazol-3-ylamine
N,N-Diisopropylethylamine (1.7 mL, 7.99 mmol) was added to a mixture of phenyl hydrazine hydrochloride (1.5 g, 10.39 mmol) and 4,4-dimethyl-3-oxopentane nitrile (1.0 g, 7.99 mmol) in ethanol (15 mL) and the mixture was heated under reflux for 18 hours. The cooled mixture was then concentrated to low volume and partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluding with heptanes:ethyl acetate, 75:25, to afford the title compound as a pale orange oil that crystallized on standing (1.21 g, 70% yield).
With acetic acid In ethanol Reflux;
Synthesis of 3-t-butyl-1-phenyl-1H-pyrazol-5-amine 5a-c
General procedure: A solution of pivoloylacetonitrile 4 (1.0 g, 8.0 mmol). substituted phenylhydrazine hydrochlorides (0.83 mL, 8.39 mmol) and a few drops of glacial acetic acid in ethanol were refluxed in absolute alcohol overnight. The solvent was evaporated by vacuum distillation and the residue was washed with petroleum ether. The solid was taken in ethyl acetate and washed with aqueous NaHCO3. The organic layer was further washed with brine, water and evaporated to yield the desired product as a crystalline solid in 80-90% yield (~ 89% )24.
With N-ethyl-N,N-diisopropylamine;Heating / reflux;
1) Pyrazole Synthesis: A solution of ethyl hydrazinyl acetate hydrochloride (7.49 mmol) and DIEA (6.51 mmol) in toluene was stirred at room temperature for 15 minutes. 4,4-Dimethyl-3- oxopentanenitrile (7.49 mmol) was added, and the reaction was refluxed overnight. The reaction mixture was quenched with water and the resulting mixture was extracted with ethyl acetate (3 x 30 niL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under vacuum to afford the desired aminopyrazole as a brown solid. This material was used in the next step without further purification.
(1) A solution of pivaloylacetonitrile (4.60 g) and <strong>[36600-66-5]4-tert-butylphenylhydrazine hydrochloride</strong> (3.167 g) in a mixed solvent of ethyl acetate (63 mL) and methanol (7 mL) was heated under reflux for 12 hr. The solvent of the reaction mixture was evaporated, and the residue was poured into ethyl acetate. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried, and the solvent was evaporated. The residue was purified by column chromatography to give 3-tert-butyl-1-(4-tert-butylphenyl)-1H-pyrazol-5-amine (3.54 g). 1H-NMR (300 MHz, CDCl3) deltappm 1.21 (9 H, s) 1.31 (9 H, s) 5.15 (2 H, br s) 5.36 (1 H, s) 7.46 (4 H, m)
2-(5,6-dimethoxy-3,3-dimethyl-1-indanylidene)-4,4-dimethyl-3-oxo-pentanonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With ammonium acetate; propionic acid; In 5,5-dimethyl-1,3-cyclohexadiene;
Example 1 2-(5,6-Dimethoxy-3,3-dimethyl-1-indanylidene)-4,4-dimethyl-3-oxo-pentanonitrile 44g (0.2 mol) of <strong>[4136-26-9]5,6-dimethoxy-3,3-dimethyl-1-indanone</strong>, 25 g (0.2 mol) of pivaloylacetonitrile, 32 g of propionic acid and 17 g of ammonium acetate are mixed in 80 g of xylene and heated at 120 C. for 7 hours. After the system has been cooled to room temperature and the organic phase has been washed, the xylene is distilled off, and the crude product which remains is recrystallized in methanol. Yield: 50% theory; E1/1730 (lambdamax373 nm).
With hydrogenchloride; n-butyllithium In tetrahydrofuran; ethanol
1 1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea
EXAMPLE 1 1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea A mixture of 4-methylphenyl hydrazine hydrochloride (10.0 g) and 4,4-dimethyl-3-oxopentanenitrile (8.67 g) in 150 mL ethanol and 7 mL concentrated HCl was heated at reflux overnight, cooled to room temperature, basified to pH 12 with alkali and extracted with diethyl ether. The combined organic extracts were washed with brine and dried (MgSO4). Removal of the volatiles in vacuo left a residue which was triturated with hot petroleum ether (100 mL) and provided 12.5 g of LXVII. To a mixture of 4-amino-1-naphthol hydrochloride (LXIII) (172.1 g) in 750 mL anhydrous THF at -78° C. was added dropwise over 60 min n-butyl lithium (490 mL of a 1.60 M solution in hexanes). After the addition was complete the mixture was allowed to warm to room temperature and then cooled to -78° C. and di-tert-butyl dicarbonate ((BOC)2O, 192 g) in 200 mL THF was added over 20 min. The mixture was slowly warmed to room temperature and stirred for 3 h and most of the volatiles removed in vacuo. The residue was diluted with ethyl acetate (1 L) and washed with water (2*200 mL) and brine (200 mL) and filtered through celite and dried (MgSO4). Removal of the volatiles in vacuo provided LXIV (226.1 g).
(XIV) Pyrazole synthesis; Synthesis 81; 3-terf-Butyl-1-(2,4-difluorophenyl)-1H-pyrazol-5-amine; Method K. <strong>[40594-29-4]2,4-difluorophenylhydrazine hydrochloride</strong> (500 mg, 2.8 mmol) and 4,4- dimethyl-3-oxopentanenitrile (386 mg, 3.08 mmol) were dissolved in a 0.2 M ethanolic solution of HCI (15 ml_). The solution was heated under reflux for 12 hours. After cooling to room temperature, the mixture was basified with 1 M NaOH until pH 12. EtOAc was added (40 ml_) and the aqueous layer was discarded. The solvents were evaporated under reduced pressure and the resulting yellow solid was dissolved in EtOAC (40 ml_). The solution was washed with water and brine, and then dried over MgSO4. Evaporation of the solvent in vacuo afforded the title compound (695 mg, quantitative yield) as a yellow solid. 1H-NMR (delta, ppm, DMSO-d6): 1.19 (s, 9H, t-Bu), 5.08 (bs, 2H, NH2), 5.30 (s, 1 H, Hpyz,4), 7.17 (m, 1 H, Harom), 7.38-7.53 (m, 2H, Harom).
With hydrogenchloride; sodium hydroxide; hydroxylamine sulfate; In water;
EXAMPLE 2 To a suspension of pivaloylacetonitrile (25.03 g) in water (400 ml) is added 96% sodium hydroxide (9.17 g). Hydroxylamine sulfate (18.06 g) is added to the resulting solution at 27 C. The mixture is stirred at room temperature for 30 minutes, adjusted to pH 8 with 10% sulfuric acid (0.97 g), stirred at 60 C. for 22 hours, cooled at 20 C., mixed with conc. hydrochloric acid (7.90 g), and heated at 50 C. for 2 hours. Conc. hydrochloric acid (14.18 g) is added to the mixture, which is heated at 100 C. for 1 hour. After cooling, the reaction mixture is adjusted to pH 11 with 30% sodium hydroxide (49.8 g) and shaken with chloroform. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated to remove chloroform, whereby 3-amino-5-t-butylisoxazole (24.16 g) is obtained. Yield, 86.2%. Purity, 95.4%. m.p. 103.5-109 C. The mother liquor after extraction is mixed with the washings, adjusted to pH 1 with conc. hydrochloric acid and extracted with benzene. The organic layer is treated in a conventional manner to give 3-t-butyl-5-isoxazolone (2.48 g; yield, 8.8%).
85.9%
With potassium hydroxide; hydroxylamine sulfate; In water;
EXAMPLE 5 To a suspension of pivaloylacetonitrile (1.252 g) and 86% potassium hydroxide (0.717 g) in water (20 ml) is added hydroxylamine sulfate (0.903 g) at 25 C. and the mixture is stirred for 3 minutes. pH 8.30. The reaction mixture is treated as in Example 2 to give 3-amino-5-t-butylisoxazole (1.204 g). Yield, 85.9%. Purity, 95.8%. The mother liquor after extraction gives 3-t-butyl-5-isoxazolone (0.153 g; yield, 10.8%).
85.7%
With sodium carbonate; hydroxylamine sulfate; In water;
EXAMPLE 3 A suspension of pivaloylacetonitrile (12.52 g), sodium carbonate (8.74 g) and water (200 ml) is stirred and mixed with hydroxylamine sulfate (9.03 g) at 25 C. pH 7.11. The reaction mixture is treated as in Example 2 to give 3-amino-5-t-butylisoxazole (12.01 g). Yield, 85.7%. Purity, 95.8%. The mother liquor after extraction gives 3-t-butyl-5-isoxazolone (1.42 g; yield, 10.1%).
With hydroxylamine sulfate; triethylamine; In water;
EXAMPLE 4 A suspension of pivaloylacetonitrile (12.52 g) and triethylamine (11.27 g) in water (200 ml) is stirred and mixed with hydroxylamine sulfate (9.03 g). pH 8.22. The reaction mixture is treated as in Example 2 to give 3-amino-5-t-butylisoxazole (11.45 g; yield, 81.7%). The mother liquor after extraction gives 3-t-butyl-5-isoxazolone (1.72 g; yield, 12.2%).
2,2-dimethyl-3-amino-3-butenyl thiocarboxamide[ No CAS ]
[ 59997-51-2 ]
[ 89151-73-5 ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; hydrogen sulfide; ammonia; dihydrogen peroxide In ethanol; dichloromethane
120.A (A)
(A) Preparation of 3-(1,1-dimethylethyl)-5-aminoisothiazole A mixture of 50.0 g of cyanomethyl tert.butyl ketone in 250 ml of ethanol containing 200 ml of ammonia was heated at 150° C. for sixteen hours. The reaction mixture was cooled to room temperature and the solvent was removed by evaporation under reduced pressure. The residue was dissolved in 330 ml of dichloromethane and diluted with 0.7 g of potassium hydroxide and 52 ml of hydrogen sulfide. The reaction mixture was heated at 80° C. for twenty-four hours, and then cooled and concentrated to dryness by evaporation of the solvent. The product was identified as 71 g of 2,2-dimethyl-3-amino-3-butenyl thiocarboxamide. An 800 mg portion of the product thus obtained was dissolved in 25 ml of ethanol containing 5 ml of 30% hydrogen peroxide. The reaction mixture was stirred for twenty minutes, and then concentrated to dryness by evaporation to provide (3-(1,1-dimethyl-ethyl)-5-aminoisothiazole.
(4-methoxyphenyl)hydrazine hydrochloride 308 (1 .5g, 8.59mmol, 1 .0eq) and pivaloyl acetonitrile (1 .1 g, 8.59mmol, 1 .0eq) were reacted at reflux for 18h. The solution was basified with hydrogenocarbonate, filtrated and evaporated. The residue was purified by flash chromatography over silica gel using cyclohexane and ethyl acetate to afford expected compound 309 as orange oil (2.1 g, quantitative yield).
87%
With hydrogenchloride; In ethanol; for 48h;Reflux;
General procedure: A solution of 4-tolyllhydrazine hydrochloride(5.20 g, 33 mmol) and pentylacyl acetonitrile (3.75 g, 30 mmol) in 0.4 M ethanolic solution of HCl(100 mL) was heated under reflux during 48 h. After cooling to room temperature, 1M NaOH wasadded to the mixture until the pH reached 10-11. The mixture was partitioned between water and ethylacetate. The water phase was extracted twice with dichloromethane. The organic phases werecombined and washed with water and brine, then dried with Na2SO4. Evaporation of the solvent invacuo afforded the crude product, which was subjected to recrystallization from ethyl acetate andpetroleum ether to produce compound 25a as a white solid (5.88 g, 86% yield).
80%
In ethanol; at 80℃;
General procedure: A solution of the corresponding substituted phenylhydrazine hydrochloride (1 equiv.) and pivaloylacetonitrile (1.2 equiv.) was stirred overnight at 80 C in ethanol. The solution was extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered, and evaporated to dryness.
70%
With triethylamine; In toluene;
EXAMPLE W Solid 4-methoxyphenylhydrazine hydrochloride (25.3 g) was suspended in toluene (100 mL) and treated with triethylamine (20.2 g). The mixture was stirred at RT for 30 min and treated with pivaloylacetonitrile (18 g). The reaction was heated to reflux and stirred overnight. The hot mixture was filtered, the solids washed with hexane and dried in vacuo to afford 3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-amine (25 g, 70%). 1H NMR MS-d6): δ 7.5 (d, 2H), 7.0 (d, 1H), 6.4 (s, 1H), 6.1 (s, 2H), 3.9 (s, 3H), 1.3 (s, 9H).
70%
With triethylamine; In toluene;
Example W Solid 4-methoxyphenylhydrazine hydrochloride (25.3 g) was suspended in toluene (100 mL) and treated with triethylamine (20.2 g). The mixture was stirred at RT for 30 min and treated with pivaloylacetonitrile (18 g). The reaction was heated to reflux and stirred overnight. The hot mixture was filtered, the solids washed with hexane and dried in vacuo to afford 3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-amine (25 g, 70%). 1H NMR (DMSO-d6): δ 7.5 (d, 2H), 7.0 (d, 1H), 6.4 (s, 1H), 6.1 (s, 2H), 3.9 (s, 3H), 1.3 (s, 9H).
N1-(4-Methoxyphenyl)-5-amino-3-tert-butylpyrazole: A mixture of 4-methoxyphenylhydrazine hydrochloride (3.5 g), 4,4-dimethyl-3-oxopentanenitrile (2.5 g), EtOH (30 mL), and AcOH (1 mL) was heated at the reflux temperature for 3 h, cooled to room temp., and poured into a mixture of Et2O (100 mL) and a 10% Na2CO3 solution (100 mL). The organic layer was washed with a saturated NaCl solution, dried (MgSO4) and concentrated under reduced pressure. The solid residue was washed with pentane to afford the desired pyrazole as a pale brown solid. (4.25 g): 1H-NMR (DMSO-d6) δ 1.18 (s, 9H); 3.78 (s, 3H); 5.02 (br s, 2H); 5.34 (s, 1H); 6.99 (d, J=8 Hz, 2H); 7.42 (d, J=8 Hz, 2H).
A mixture of 4-methoxyphenylhydrazine hydrochloride (3.5 g), 4,4-dimethyl-3-oxopentanenitrile (2.5 g), EtOH (30 mL), and AcOH (1 mL) was heated at the reflux temperature for 3 h, cooled to room temp., and poured into a mixture of Et2O (100 mL) and a 10% Na2CO3 solution (100 mL). The organic layer was washed with a saturated NaCl solution, dried (MgSO4) and concentrated under reduced pressure. The solid residue was washed with pentane to afford the desired pyrazole as a pale brown solid. (4.25g): 1H-NMR (DMSO-d6) δ 1.18 (s, 9H); 3.78 (s, 3H); 5.02 (br s, 2H); 5.34 (s, 1H); 6.99 (d, J=8 Hz, 2H); 7.42 (d, J=8 Hz, 2H).
In a 250 mL pre-flask was added 100 mL of ethanol,(30 mmol) of pivaloylacetonitrile,(33. 63 mmol) of 4-methylphenylhydrazine,3. 6 mL of concentrated hydrochloric acid was added dropwise with stirring, heated under reflux for 8 hours,Cooled, concentrated, the residue adjusted with dilute sodium hydroxide PH10-11,Extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, concentrated,The resulting solid was recrystallized from ethyl acetate / petroleum ether to give white crystals C,Yield 80.3%. 5-tert-butyl-2-p-methylphenyl-3-aminopyrazole (3. 5 mmolC) was placed in 100 ml three-necked flask and dissolved in 30 ml of tetrahydrofuran. The three-necked flask was allowed to cool to -20 C, stirring in batches by adding 2. 9g sodium bicarbonate, 15min, dropwise dropwise chloroformic acid trichloroethyl ester(3. 5 mmol),Control solution temperature does not exceed C,After completion of the dropwise addition, the mixture was stirred for 30 min and then heated to 0 C for 12 h. After completion of the reaction, the mixture was filtered and the residue was rinsed with ethyl acetate and the filtrate was concentrated to yield 85%.
80.3%
With hydrogenchloride; In ethanol; water; for 8h;Reflux;
In a 250 mL round botom flask, 100 mL of ethanol was added, (30 mmol) of pivaloylacetonitrile, (33.63 mmol) of 4-methylphenylhydrazine, A solution of 3.6 mL of concentrated hydrochloric acid was added dropwise with stirring,Heated to reflux for 8 hours, cool down, concentrate, The residue was adjusted to pH 10-11 with dilute sodium hydroxide, Extracted three times with ethyl acetate, Dried over anhydrous sodium sulfate, concentrate, The resulting solid was recrystallized from ethyl acetate / petroleum ether to give white crystals C, Yield 80.3%. 5-tert-butyl-2-p-methylphenyl-3-aminopyrazole (3.5 mmolC) was placed in a 100 ml three-Dissolved in 30 ml of tetrahydrofuran, Place the three-necked flask in a cryogenic tank to cool to -20 C, 2.9 g of sodium bicarbonate was added in portions with stirring, After 15 min, A solution of trichloroethyl chloroformate (3.5 mmol) was added dropwise, Control the solution temperature does not exceed 0 deg C, After dripping, Continue stirring for 30min, And then heated to 0 C for 12 h. After completion of the reaction, The mixture is filtered, The residue was washed with ethyl acetate, The filtrate was concentrated, Yield 85%.
80.3%
With hydrogenchloride; for 8h;Reflux;
In 250 ml bottle eggplant adding 100 ml ethanol, (30mmol) special fifth heavenly stem acyl acetonitrile, (33.63mmol) 4 - methyl phenyl hydrazine, stirring next adds by drops 3.6 ml concentrated hydrochloric acid, heating reflux for 8 hours, cooling, concentrated, the residue with dilute sodium hydroxide to adjust the pH 10 - 11, ethyl acetate extraction three times, dried with anhydrous sodium sulfate, concentrated, the obtained solid ethyl acetate/petroleum ether recrystallization to obtain white crystal C, yield 80.3%. 5 - tert-butyl -2 - methylphenyl -3 - amino pyrazole (3.5mmolC) in 100 ml in three-necked bottle, to 30 ml tetrahydrofuran is dissolved, the low temperature troughthree-necked bottle is lowering the temperature to -20 C, stirring in batches under the adding 2.9g sodium bicarbonate, 15min after, little by chlorination formic acid trichloroethyl (3.5mmol), control solution at a temperature of not more than 0 C, after dropping, continuing to stir 30min, then heating up to 0 C reaction 12h. The completion of the reaction, the mixture filtration, the filter residue washed ethyl acetate, the filtrate is concentrated, yield 85%.
In toluene; at 20℃; for 12h;Heating / reflux;
The title compound is prepared according to a published literature procedure (see J. Med. Chem. 2002, 45, 2994-3008.) 3.5 g (27.8 mMol) of pivaloylacetonitrile are added to a solution of 3.4 g (27.8 mMol) p-tolylhydrazine in 50 mL of toluene at rt, and the resulting yellow solution is heated to and kept under reflux for 12 h. After completion, the reaction mixture is concentrated, and the resulting crude product is purified by flash chromatography (SiO2, 100% CH2Cl2) to give the title compound as a yellow solid.
In toluene;Heating / reflux;
A solution of 4-methylphenylhydrazine (0.90mL) and 4,4-dimethyl-3-oxopentanenitrile (1.0g) in toluene (3mL) was refluxed overnight. The reaction mixture was concentrated and the residue was purified by column to give the title compound (1.53g).
Stage #1: trimethylacetylacetonitrile; 4-fluorophenylhydrazine With acetic acid In ethanol for 18h; Heating / reflux;
Stage #2: With sodium hydrogencarbonate In ethanol; water; ethyl acetate
4
To a solution of 4,4-dimethyl-3-oxopentanenitrile (7.54 g, 59.7 mmol) and 4- fluorophenylhydrazine (10.0 g, 59.7 mmol) in anhydrous EtOH (100 mL) was added acetic acid (4.8 mL, 83.5 mL) dropwise. The reaction was stirred at reflux under N2 for 18 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc (150 mL) and aqueous saturated NaHCOβ solution (100 mL). The organic layer was separated, washed successively with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified by MPLC (eluting with 10 to 15% EtOAc/hexanes) to give 12.4 g (89 %) of the desired product. 1H-NMR (DMSO- cfe) δ 7.59-7.53 (m, 2H), 7.30-7.22 (m, 2H), 5.36 (s, 1 H), 5.19 (br s, 2H), 1.19 (s, 9H); LC-MS m/z [M+H]+ 233.9, RT 1.95 min.
In toluene at 20℃; for 12h; Heating / reflux;
2.3
Intermediate 2.3 5-fert-Butyl-2-(4-fluor<>-phenyl)-2H-pyrazol-3-ylamine; The title compound is prepared according to a published literature procedure (see J. Med. Chem. 2002, 45, 2994-3008.) 4.17 g (32.3 mMol) of pivaloylacetonitrile are added to a solution of 4.20 g (32.3 mMol) 4-fluoro-phenylhydrazine in 150 mL of toluene at rt, and the resulting yellow solution is heated to and kept under reflux for 12 h. After completion, the reaction mixture is concentrated, and the resulting crude product is purified by flash chromatography (SiO2, 100 % CH2CI2) to give the title compound as a yellow solid. MS: [M+1]+ = 234.3; 1HNMR (CDCI3) 7.59 (d, 2H), 7.10 (d, 2H), 5.58 (s, 1 H), 3.62 (brs, 2H, NH2), 1.32 (s, 9H).
A mixture of <strong>[87565-98-8]3-hydrazinobenzoic acid hydrochloride</strong> (200 g, 1.06 mol) and 4,4- dimethyl-3-oxopentanenitrile (146 g, 1.167 mol) in EtOH (2 L) was heated at reflux overnight. The reaction solution was evaporated under reduced pressure. The residue was purified by column chromatography to give 3-(5-amino-3-t-butyl-pyrazol-1-yl)-benzoic acid ethyl ester (116 g, 40%) as a white solid together with 3-(5-amino-3-t-butyl-pyrazol-1- yl)benzoic acid (93 g, 36%). 3-(5-amino-3-t-butyl-pyrazol-1-yl)benzoic acid and ethyl ester.
12.1
To a solution of cyclopropylmethanol (125 g) and triethylamine (315 ml) in chloroform (500 ml), methanesulfonyl chloride (175 ml) was added under ice cool for 1.5 hours. The mixture was stirred at room temperature for 2 hours. To the reaction solution, water was added and the reaction solution was extracted with chloroform, washed sequentially with water and saturated brine, dried over anhydrous magnesium sulfate, and filtrated. Thereafter, the filtrate was concentrated under vacuum. The residue obtained (232 g) was dissolved in ethanol (500 ml). To this, hydrazine monohydrate (500 g) was added at room temperature and stirred for 17 hours. After the solvent was distilled off under vacuum, the residue was extracted with chloroform, dried over anhydrous magnesium sulfate, and filtrated. The filtrate was concentrated under vacuum. The residue of a yellow oily substance (68 g) obtained was dissolved in ethanol (610 ml). To this, 4,4-dimethyl-3-oxopentanenitrile (99 g) was added at room temperature and then refluxed for 4 hours. After the solvent was removed under vacuum, the residue was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=5:1) and recrystallized from ethyl acetate/n-hexane to obtain a colorless solid substance of 3-amino-5-t-butyl-2-cyclopropylmethyl)pyrazole (80 g). 1H-NMR (200 MHz, CHLOROFORM-d) d ppm; 0.26-0.41 (m, 2H), 0.49-0.62 (m, 2H), 1.11-1.27 (m, 1H), 1.26 (s, 9H) 3.42 (br. s, 2H), 3.86 (d, J = 6.2 Hz, 2H), 5.42 (s, 1H) MS(ESI)(Positive) m/z; 194 (M+H)+ Melting point: 69.5-70.5°C
m-Tolylhydrazine (3.81 g, 31 mMol) and pivaloylacetonitrile (3.91 g 31 mMol) are dissolved in toluene (30 mL) and refluxed for 12 h. After cooling and removal of all volatiles the crude product is purified by flash chromatography (SiO2, 100% CH2Cl2) to give the title compound. MS: [M+1]+=230.11; 1H-NMR (CDCl3): 7.39 (s, 1H), 7.37 (m, 2H), 7.15 (m, 1H), 5.43 (s, 1H), 3.71 (bs, 2H, NH2), 2.39 (s, 3H), 1.34 (s, 9H).
Stage #1: 2-methylquinolin-6-amine With hydrogenchloride; sodium nitrite In water at 0℃; for 1h;
Stage #2: With hydrogenchloride; tin(ll) chloride In water at 0 - 20℃; for 3h;
Stage #3: trimethylacetylacetonitrile In ethanol; water Heating / reflux;
B.19
Example B19 A solution of sodium nitrite (502 mg, 7.27 mmol) in H2O (8 ml) was added dropwise to a well-stirred 0° C. mixture of 2-methylquinolin-6-amine (1.00 g, 6.32 mmol) in conc. HCl (10 ml). The resulting mixture was stirred at 0° C. for 1 h. Tin(II)chloride dihydrate (6.13 g, 27.2 mmol) in conc. HCl (8 ml) was added and stirring was continued at 0° C. for 1 h and then RT for 2 h. Ethanol (60 ml) and 4,4-dimethyl-3-oxopentanenitrile (1.03 g, 8.22 mmol) were added and the mixture was heated at reflux overnight. The completed reaction mixture was concentrated in vacuo and diluted with ethyl acetate (100 mL). The mixture was cooled in an ice/water bath and made basic (pH~8) with solid sodium hydroxide. The solution was filtered through Celite, and the filter cake was washed with water (50 mL) and ethyl acetate (100 mL). The organic phase was separated, washed with brine, dried Na2SO4), and concentrated to yield a foam. The foam was stirred in ether (50 mL) and allowed to stand for several hours. The resultant solid was collected by filtration and dried in vacuo to yield 3-tert-butyl-1-(2-methylquinolin-6-yl)-1H-pyrazol-5-amine (428 mg, 24% yield). MS (ESI) m/z: 281.2 (M+H+).
24%
Stage #1: 2-methylquinolin-6-amine With hydrogenchloride; tin(II) chloride dihdyrate; sodium nitrite In water at 0 - 20℃; for 3h;
Stage #2: trimethylacetylacetonitrile In ethanol; water Reflux;
B19
A solution of sodium nitrite (502 mg, 7.27 mmol) in H20 (8 ml) was added dropwise to a well-stirred 0 °C mixture of 2-methylquinolin-6-amine (1.00 g, 6.32 mmol) in cone. HC1 (10 ml). The resulting mixture was stirred at 0 °C for 1 h. Tin(II)chloride dihydrate (6.13 g, 27.2 mmol) in cone. HC1 (8 ml) was added and stirring was continued at 0 °C for 1 h and then RT for 2h. Ethanol (60 ml) and 4,4-dimethyl-3- oxopentanenitrile (1.03 g, 8.22 mmol) were added and the mixture was heated at reflux overnight. The completed reaction mixture was concentrated in vacuo and diluted with ethyl acetate (100 mL). The mixture was cooled in an ice/water bath and made basic (pH~8) with solid sodium hydroxide. The solution was filtered through Celite, and the filter cake was washed with water (50 mL) and ethyl acetate (100 mL). The organic phase was separated, washed with brine, dried (Na2SC>4), and concentrated to yield a foam. The foam was stirred in ether (50 mL) and allowed to stand for several hours. The resultant solid was collected by filtration and dried in vacuo to yield 3-tert-butyl-l-(2- methylquinolin-6-yl)-lH-pyrazol-5-amine (428 mg, 24% yield). MS (ESI) m z: 281.2 (M+H+).
Example 47 To a suspension of <strong>[53312-81-5]5-amino-2-fluorobenzonitrile</strong> (1.00 g, 7.38 mmol) in conc HCl (15 mL) at 0 C. was added a solution of NaNO2 (0.64 g, 9.28 mmol) in water (15 mL) slowly over 15 min. The resultant mixture was stirred for 90 min at 0 C. A solution comprised of SnCl2.2H2O (3.37 g, 14.9 mmol), conc HCl (5 mL) and water (5 mL) was added drop wise over 20 min. The mixture was stirred for 2 h at 0 C., and was extracted with EtOAc (4*25 mL). The aqueous portion was cooled with an ice bath and cautiously treated with 70 mL of 3 M NaOH (70 mL) to a final pH of 5. The aqueous was extracted with EtOAc (2*50 mL). All organics were combined and concentrated in vacuo to afford a brown oil (2.58 g), which was combined with pivaloylacetonitrile (1.00 g, 8.0 mmol) in isopropanol (15 mL). The resultant solution was heated to reflux for 28 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc (30 mL) and washed with water (20 mL), satd aq NaHCO3 (20 mL), water (20 mL) and brine (20 mL). The aqueous was further extracted with EtOAc (2*20 mL). The combined organics were dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel to provide 5-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)-2-fluorobenzonitrile (1.24 g, 65% yield). 1H NMR (400 MHz, DMSO-d6) delta 8.05 (m, 1H), 7.97 (m, 1H), 7.61 (t, J=9.0 Hz, 1H), 5.43 (s, 1H), 5.42 (s, 2H); MS (ESI) m/z: 259.3 (M+H+).
65%
To a suspension of <strong>[53312-81-5]5-amino-2-fluorobenzonitrile</strong> (1.00 g, 7.38 mmol) in cone HCl (15 mL) at 0 C was added a solution of NaN02 (0.64 g, 9.28 mmol) in water (15 mL) slowly over 15 min. The resultant mixture was stirred for 90 min at 0 C. A solution comprised of SnCl2.2H20 (3.37 g, 14.9 mmol), cone HCl (5 mL) and water (5 mL) was added drop wise over 20 min. The mixture was stirred for 2 h at 0 C, and was extracted with EtOAc (4 x 25 mL). The aqueous portion was cooled with an ice bath and cautiously treated with 70 mL of 3 M NaOH (70 mL) to a final pH of 5. The aqueous was extracted with EtOAc (2 x 50 mL). All organics were combined and concentrated in vacuo to afford a brown oil (2.58 g), which was combined with pivaloylacetonitrile (1.00 g, 8.0 mmol) in isopropanol (15 mL). The resultant solution was heated to reflux for 28 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc (30 mL) and washed with water (20 mL), satd aq NaHC03 (20 mL), water (20 mL) and brine (20 mL). The aqueous was further extracted with EtOAc (2 x 20 mL). The combined organics were dried (MgSC^), concentrated in vacuo and purified by chromatography on silica gel to provide 5-(5-amino-3-tert-butyl-lH-pyrazol-l-yl)-2- fiuorobenzonitrile (1.24 g, 65% yield). FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO-c) delta 8.05 (m, 1 H), 7.97 (m, 1 H), 7.61 (t, J = 9.0 Hz, 1 H), 5.43 (s, 1 H), 5.42 (s, 2 H); MS (ESI) m/z: 259.3 (M+H+).
A solution of 4,4-dimethyl-3-oxovaleronitrile (1.75 g, 14.0 mmol) in EtOH (10 mL) was added to a slurry of tert-butylhydrazine hydrochloride (3.5 g. 28.1 mmol) in EtOH (35 mL) and the solution was heated to reflux with stirring for 18 h. The solution was cooled, concentrated, and the residue was partitioned between sat. aq NaHCO3 (30 mL) and EtOAc (30 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 × 20 mL). The organic layers were combined, washed with brine (20 mL), dried (MgSO4), and the solvent removed to give 6f as a pale orange solid; yield: 1.8 g (66percent); mp 67?69 °C (Lit. 9a mp 64?66 °C).
20%
With triethylamine; In ethanol; at 100℃; for 96h;
A solution of pivaloylacetonitrile (300 mg, 2 mmol, 1.0 equiv), triethylamine (1.16 mL, 8.3 mmol, 3.2 equiv), and tert-butylhydrazine hydrochloride (1.03 g, 8.3 mmol, 3.2 equiv) in 10 mL of ethanol was heated at 100° C. in a sealed tube. After 4 days, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified via automated flash chromatography (40 g SiO2, ethyl acetate to 20percent methanol in ethyl acetate) to afford the product as an off-white solid (123 mg, 20percent).
3-tert-butyl-1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-5-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
Synthesis 127 3-ferf-butyl-1 -(4-(methylsulfonyl)phenyl)-1 /-/-pyrazol-5-amine<strong>[17852-67-4]4-(methylsulfonyl)phenylhydrazine hydrochloride</strong> (1.133 g, 5.09 mmol) and 4,4-dimethyl- 3-oxopentanenitrile (0.697 g, 5.57 mmol) were weighed into a 100 ml_ RBF. 0.2 M HCI in EtOH (42 mL) was added and the suspension was heated to reflux for 27 h, during which time all solids gradually dissolved to give a yellow solution. The solution was diluted with 1 M NaOH(aq) (-16 mL) to pH 12-13, EtOAc (70 mL) was added and the biphasic system <n="171"/>was vigorously stirred for 5 min. The organic layer was isolated, dried (MgSO4), filtered and concentrated to give a yellow crystalline solid. Yield: 1.42 g (95%).1H-NMR (DMSOd6), delta (ppm), J (Hz): 1.23 (s, 9H, tert- Bu), 3.22 (s, 3H, Me), 5.45 (br s, 2H, NH2), 5.46 (s, 1H, HPyz), 7.90 (d, 2H, J=8.7, Harom), 7.98 (d, 2H, J=8.7, Harom); 13C-NMR (DMSO-d6), delta (ppm), J (Hz): 30.0, 31.9, 43.7, 88.3, 121.6, 128.1 , 136.7, 143.8, 148.0, 162.2; LC-MS (1.98 min): m/z 294.1 (M+H, 100).
To a solution of Example 95A (9.1 g, 33.7 mmol) in EtOH (50 mL) was added hydrazine hydrate (3.3 mL, 67.3 mmol). The mixture was warmed to reflux (85 C.) and was allowed to stir for 20 hours. The mixture was cooled to ambient temperature then 4,4-dimethyl-3-oxopentanenitrile (8.4 g, 67.3 mmol) was added and the mixture was again warmed to reflux (85 C.) and was allowed to stir for 6 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in CH2Cl2 (30 mL) and saturated aqueous NaHCO3 (20 mL) was added slowly. The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 50% hexanes/EtOAc to 100% EtOAc to 9:1:0.1 EtOAc:MeOH:Et3N) provided the title compound (5.2 g, 21.9 mmol, 65% yield). MS (DCI/NH3) m/z 238 (M+H)+
Multi-step reaction with 4 steps
1.1: sodium acetate / ethanol / 12 - 25 °C
2.1: ethanol / 69 - 72 °C
2.2: 40 - 70 °C
3.1: dmap; N-ethyl-N,N-diisopropylamine; trichlorophosphate / acetonitrile / 2 h / 35 °C / Industry scale
3.2: 1 h / 20 °C / Industry scale
4.1: 2-methyltetrahydrofuran / 16 h / 20 °C / Industry scale
a. 5-tert-Butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazol-3-ylamine (Intermediate Ja) A black solution of <strong>[60481-51-8]3,4-dimethylphenyl hydrazine hydrochloride</strong> (Apollo, 1.73 g, 10.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.38 g, 11.0 mmol) in EtOH (20 mL) was stirred at reflux for 5 h. The cooled solution was concentrated in vacuo, redissolved in diethyl ether (20 mL) and washed with aqueous NaOH solution (1M, 20 mL). The aqueous was extracted with diethyl ether (2*20 mL), then the combined organics washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo to leave the title compound (2.18 g, 90percent). LCMS (Method 3): Rt 2.75 min, m/z 244 [MH+].
90%
In ethanol; for 5h;Reflux;
A black solution of <strong>[60481-51-8]3,4-dimethylphenyl hydrazine hydrochloride</strong> (Apollo, 1.73 g, 10.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.38 g, 11.0 mmol) in EtOH (20 mL) was stirred at reflux for 5 h. The cooled solution was concentrated in vacuo, redissolved in diethyl ether (20 mL) and washed with aqueous NaOH solution (1M, 20 mL). The aqueous was extracted with diethyl ether (2 x 20 mL), then the combined organics washed with brine (20 mL), dried (Na2S04), filtered and concentrated in vacuo to leave the title compound (2.18 g, 90percent). LCMS (Method 3): Rt 2.75 min, m/z 244 [MH+].
490 mg
With triethylamine; In toluene; for 5h;Reflux;
Example 62 3-(tert-butyl)-1-(3,4-dimethylphenyl)-1H-pyrazol-5-amine To a solution of pivaloylacetonitrile (400 mg) in toluene (10 mL) were added <strong>[60481-51-8]3,4-dimethylphenylhydrazine hydrochloride</strong> (520 mg) and triethylamine (0.4 mL) and refluxed with heating for 5 hours. The reaction mixture was added with a saturated sodium hydrogen carbonate aqueous solution. The obtained organic layer was washed with a saturated sodium chloride aqueous solution. The obtained organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified on silica gel column chromatography (hexane : ethyl acetate = 4 : 1) to give the titled compound (490 mg) having the following physical data. TCL : Rf 0.41 (Hexane : Ethyl Acetate = 4 : 1).
Stage #1: trimethylacetylacetonitrile; 4-(trifluoromethoxy)phenylhydrazine hydrochloride With hydrogenchloride In ethanol; water monomer for 18h; Reflux;
Stage #2: With sodium hydroxide In ethanol; water monomer
A27
Intermediate A27: 3-fert-Butyl-1 -(4-(trifluoromethoxy)phenyl)-1H-pyrazol-5-amine.Intermediate A27 A solution of (4-(trifluoromethoxy)phenyl)hydrazine hydrochloride (1.83 g, 8.01 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.10 g, 8.81 mmol) in a mixture of cone hydrochloric acid (12 M, 2.0 mL) and EtOH (20 mL) was heated at reflux for 18 hr. The mixture was cooled to RT and was partitioned between aq. NaOH (2.0 M, 50 mL) and ether (100 mL). The organic layer was separated and was washed with brine (100 mL) and then dried and evaporated in vacuo to afford the title cmpound, Intermediate A27, as a yellow solid (2.22 g, 91%); R' 2.29 min (Method 2); m/z 300 (M+H)+, (ES+).
90%
In toluene for 16h; Reflux;
With hydrogenchloride In ethanol for 18h; Reflux;
General procedure C for synthesis of 5-aminopyrazoles under conductive heating.
General procedure: A stirred solution of the hydrazine hydrochloride (1 eq), β-ketonitrile (1 eq) and a drop of HCl (conc.) in EtOH (10 mL) was heated at reflux for 18 h. After cooling to rtrt, the mixture was basified to pH 12 by the addition of an aqueous NaOH solution (10%) (compound 6) or a sat. NaHCO3 solution (compounds 10-17) and extracted with EtOAc (3 x30 mL). The organic extracts were combined, washed with brine (40 mL), dried over Na2SO4 and the solvent was evaporated in vacuo. Purification by flash column chromatography on SiO2 or recrystallization from a hexane/EtOAc mixture gave the desired product.
2
The coupling of phenylhydrazine 26 with acetonitriie 11 in ethanol under reflux gave 27. Coupling of 27 with benzoyl isothiocyanate yield the benzoyl thiourea 28 in excellent yield. Alkaline hydrolysis of 28 yielded thiourea 29. Reaction of bromoketone 3 with thiourea 29 afforded 30.
The coupling of 2,2,2-trifluoroethylhydrazine 10 and pivaloylacetonitrile 11 in ethanol under reflux gave 12. After coupling of 12 with benzoyl isothiocyanate followed by the alkaline hydrolysis, the resulting thiourea 14 was coupled with a-bromoketone 9 to give the desired product 15.
To a suspension of <strong>[940875-99-0]ethyl 3-hydrazinylbenzoate hydrochloride</strong> (500 mg, 2.31 mmol) in EtOH (20 mL) was added 4,4-dimethyl-3-oxopentanenitrile (318 mg, 2.54 mmol). The reaction mixture was heated to reflux for 18 hours, then cooled to ambient temperature and concentrated in vacuo. The crude product was purified by silica column chromatography, eluting with 0-5% MeOH/DCM to yield the product as a yellow oil (154 mg, 23% yield). MS (apci) m/z = 288.2 (M+H).
23%
In ethanol; for 18h;Reflux;
Intermediate PI Ethyl 3 -(5 -amino-3 -tert-butyl- 1 H- yrazol- 1 - vPbenzoate [00364] To a suspension of <strong>[940875-99-0]ethyl 3-hydrazinylbenzoate hydrochloride</strong> (500 mg, 2.31 mmol) in EtOH (20 mL) was added 4,4-dimethyl-3-oxopentanenitrile (318 mg, 2.54 mmol). The reaction mixture was heated to reflux for 18 hours, then cooled to ambient temperature and concentrated in vacuo. The crude product was purified by silica column chromatography, eluting with 0-5% MeOH/DCM to yield the product as a yellow oil (154 mg, 23% yield). MS (apci) m/z = 288.2 (M+H).
23%
In ethanol; for 18h;Reflux;
1005481 To a suspension of <strong>[940875-99-0]ethyl 3-hydrazinylbenzoate hydrochloride</strong> (500 mg, 2.31 mmol) in EtOH (20 mL) was added 4,4-dimethyl-3-oxopentanenitrile (318 mg, 2.54 mmol). The reaction mixture was heated to reflux for 18 hours, then cooled to ambient temperature and concentrated in vacuo. The crude product was purified by silica column chromatography, eluting with 0-5% MeOH/DCM to yield the product as a yellow oil (154 mg, 23% yield). MS (apci) mlz = 288.2 (M+H).
23%
In ethanol; for 18h;Reflux;
Intermediate PI Ethyl 3-(5-amino-3-tert-butyl-lH-pyrazol-l -vDbenzoate [00479] To a suspension of <strong>[940875-99-0]ethyl 3-hydrazinylbenzoate hydrochloride</strong> (500 mg, 2.31 mmol) in EtOH (20 mL) was added 4,4-dimethyl-3-oxopentanenitrile (318 mg, 2.54 mmol). The reaction mixture was heated to reflux for 18 hours, then cooled to ambient temperature and concentrated in vacuo. The crude product was purified by silica column chromatography, eluting with 0-5% MeOH/DCM to yield the product as a yellow oil (154 mg, 23% yield). MS (apci) m/z = 288.2 (M+H).
23%
In ethanol; for 16h;Reflux;
To a suspension of <strong>[940875-99-0]ethyl 3-hydrazinylbenzoate hydrochloride</strong> (500 mg, 2.31 mmol) in EtOH (20 mL) was added 4,4-dimethyl-3-oxopentanenitrile (318 mg, 2.54 mmol). The reaction mixture was heated to reflux for 18 hours, then cooled to ambient temperature and concentrated in vacuo. The crude product was purified by silica column chromatography, eluting with 0-5% MeOH/DCM to yield the product as a yellow oil (154 mg, 23% yield). MS (apci) m/z = 288.2 (M+H).
23%
In ethanol; for 18h;Reflux;
Intermediate P1 Ethyl 3 -(5 -amino-3 -tert-butyl- 1 H-pyrazol- 1 -yl)benzoate1006771 To a suspension of <strong>[940875-99-0]ethyl 3-hydrazinylbenzoate hydrochloride</strong> (500 mg, 2.31 mmol) in EtOH (20 mL) was added 4,4-dimethyl-3-oxopentanenitrile (318 mg, 2.54 mmol). The reaction mixture was heated to reflux for 18 hours, then cooled to ambient temperature and concentrated in vacuo. The crude product was purified by silica column chromatography, eluting with 0-5% MeOH/DCM to yield the product as a yellow oil (154 mg, 23% yield). MS (apci) mlz = 288.2 (M+H).
23%
In ethanol; for 18h;Reflux;
To a suspension of <strong>[940875-99-0]ethyl 3-hydrazinylbenzoate hydrochloride</strong> (500 mg, 2.31 mmol) in EtOH (20 mL) was added 4,4-dimethyl-3-oxopentanenitrile (318 mg, 2.54 mmol). The reaction mixture was heated to reflux for 18 hours, then cooled to ambient temperature and concentrated in vacuo. The crude product was purified by silica column chromatography, eluting with 0-5% MeOH/DCM to yield the product as a yellow oil (154 mg, 23% yield). MS (apci) m/z = 288.2 (M+H).
1.j03
At room temperature 4,4-dimethyl-3-oxopentanenitrile (J-ll) (1 equivalents, 5 g) was taken up in ethanol (100 mL), mixed with hydrazine hydrate (2 equivalents, 4.42 g) and refluxed for 3 h. The residue obtained after removal of the ethanol by distillation was taken up in water (100 mL) and extracted with ethyl acetate (300 mL). The combined organic phases were dried over sodium sulphate, the solvent was removed under vacuum and the product (J-ll I ) (5 g, 89 % yield) was obtained as a light red solid after recrystallisation from n- hexane (200 mL).
2 (Synthesis Example 2)
(Synthesis Example 2) [0090] 181.2 g of amino isophthalic acid (A) (manufactured by Wako Pure Chemical Industries, Ltd. / Catalog no. 322-26175)) was suspended in 1000 ml of ion-exchanged water, added with 257 mL of concentrated hydrochloric acid, and maintained in ice bath at 5°C. 116 ml of an aqueous solution of 69.7 g of sodium nitrite was added dropwise thereto (reaction solution A). 1300 ml of an aqueous solution of 378.1 g of sodium sulfite was stirred at the internal temperature of 25°C, and the reaction solution A was added thereto. After stirring for 30 minutes under this state, the internal temperature was heated up to 30°C. Then, after stirring for 60 minutes, 500 mL of hydrochloric acid was added to the reaction solution, and the internal temperature was increased up to 50°C (reaction solution B). After stirring for 90 minutes under this state, 125.2 g of pivaloylacetonitrile (manufactured by Tokyo Chemical Industry Co., Ltd / Catalog No. P 1112) and 100 mL of isopropanol were added to the reaction solution B, and then, the internal temperature was increased up to 93°C. After stirring for 240 minutes, the resultant product was cooled to room temperature, and a precipitated crystal (C) was filtered by suction, washed with 1500mL of ion-exchanged water, and subsequently with 1000mL of isopropanol, and dried (isolated yield: 223.5g. yield: 73.7%).
With hydrogenchloride; In ethanol; for 48h;Reflux;
General procedure: A solution of 4-tolyllhydrazine hydrochloride(5.20 g, 33 mmol) and pentylacyl acetonitrile (3.75 g, 30 mmol) in 0.4 M ethanolic solution of HCl(100 mL) was heated under reflux during 48 h. After cooling to room temperature, 1M NaOH wasadded to the mixture until the pH reached 10-11. The mixture was partitioned between water and ethylacetate. The water phase was extracted twice with dichloromethane. The organic phases werecombined and washed with water and brine, then dried with Na2SO4. Evaporation of the solvent invacuo afforded the crude product, which was subjected to recrystallization from ethyl acetate andpetroleum ether to produce compound 25a as a white solid (5.88 g, 86% yield).
With hydrogenchloride; In ethanol; for 48h;Reflux;
General procedure: A solution of 4-tolyllhydrazine hydrochloride(5.20 g, 33 mmol) and pentylacyl acetonitrile (3.75 g, 30 mmol) in 0.4 M ethanolic solution of HCl(100 mL) was heated under reflux during 48 h. After cooling to room temperature, 1M NaOH wasadded to the mixture until the pH reached 10-11. The mixture was partitioned between water and ethylacetate. The water phase was extracted twice with dichloromethane. The organic phases werecombined and washed with water and brine, then dried with Na2SO4. Evaporation of the solvent invacuo afforded the crude product, which was subjected to recrystallization from ethyl acetate andpetroleum ether to produce compound 25a as a white solid (5.88 g, 86% yield).
With hydrogenchloride; In ethanol; for 48h;Reflux;
General procedure: A solution of 4-tolyllhydrazine hydrochloride(5.20 g, 33 mmol) and pentylacyl acetonitrile (3.75 g, 30 mmol) in 0.4 M ethanolic solution of HCl(100 mL) was heated under reflux during 48 h. After cooling to room temperature, 1M NaOH wasadded to the mixture until the pH reached 10-11. The mixture was partitioned between water and ethylacetate. The water phase was extracted twice with dichloromethane. The organic phases werecombined and washed with water and brine, then dried with Na2SO4. Evaporation of the solvent invacuo afforded the crude product, which was subjected to recrystallization from ethyl acetate andpetroleum ether to produce compound 25a as a white solid (5.88 g, 86% yield).
65%
In ethanol; at 80℃;
General procedure: A solution of the corresponding substituted phenylhydrazine hydrochloride (1 equiv.) and pivaloylacetonitrile (1.2 equiv.) was stirred overnight at 80 C in ethanol. The solution was extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered, and evaporated to dryness.
With hydrogenchloride; In ethanol; at 80℃; for 8h;
General procedure: A solution of 4-tolyllhydrazine hydrochloride (5.20 g,33 mmol) and pentylacyl acetonitrile (3.75 g, 30 mmol) in 0.4 M ethanolic solution of HCl (100 mL)was heated under reflux during 8 h. After cooling to room temperature, 1 M NaOH was added to the mixture until the pH reached 10-11. The mixture was partitioned between water and ethyl acetate. The water phase was extracted twice with dichloromethane. The organic phases were combined and washed with water and brine, then dried with Na2SO4. Evaporation of the solvent in vacuo afforded the crude product, which was subjected to recrystallization from ethyl acetate and petroleum ether to produce compound 2a as a white solid (5.88 g,). Yield: 86.4%.
3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-amine (25a).
General procedure: A solution of 4-tolyllhydrazine hydrochloride(5.20 g, 33 mmol) and pentylacyl acetonitrile (3.75 g, 30 mmol) in 0.4 M ethanolic solution of HCl(100 mL) was heated under reflux during 48 h. After cooling to room temperature, 1M NaOH wasadded to the mixture until the pH reached 10-11. The mixture was partitioned between water and ethylacetate. The water phase was extracted twice with dichloromethane. The organic phases werecombined and washed with water and brine, then dried with Na2SO4. Evaporation of the solvent invacuo afforded the crude product, which was subjected to recrystallization from ethyl acetate andpetroleum ether to produce compound 25a as a white solid (5.88 g, 86% yield).
With hydrogenchloride; In ethanol; water; at 85℃; for 4.5h;
a. 5-tert-Butyl-2-propyl-2H-pyrazol-3-ylamine (Intermediate 23a) A stirred solution of <strong>[56795-66-5]propylhydrazine hydrochloride</strong> (0.50 g, 4.52 mmol) and 4,4-dimethyl-3-oxopentanenitrile (0.566 g, 2.77 mmol) in ethanol (6 mL) was treated with concd. HCl (1 drop) and heated at 85 C. for 4.5 h. The reaction mixture was allowed to cool overnight and then the solvent was evaporated. The residue was dissolved in dichloromethane (20 mL) and washed with saturated aqueous NaHCO3 (10 mL). The organic layer was separated using a phase separator cartridge and evaporated. The residual oil was dissolved in diethyl ether and evaporated to afford the title compound (0.776 g, 95%) as an oil that slowly solidified. 1H NMR (300 MHz, CDCl3): 0.92 (3H, t, J 7.4 Hz), 1.25 (9H, s), 1.87-1.79 (2H, sextet, J 7.4 Hz), 3.35 (2H, br s), 3.85 (2H, t, J 7.4 Hz), 5.41 (1H, s).
95%
With hydrogenchloride; In ethanol; at 85℃; for 4.5h;
A stirred solution of <strong>[56795-66-5]propylhydrazine hydrochloride</strong> (0.50 g, 4.52 mmol) and 4,4- dimethyl-3-oxopentanenitrile (0.566 g, 2.77 mmol) in ethanol (6 mL) was treated with coned. HCl (1 drop) and heated at 85 C for 4.5 h. The reaction mixture was allowed to cool overnight and then the solvent was evaporated. The residue was dissolved in dichloromethane (20 mL) and washed with saturated aqueous NaHC03 (10 mL). The organic layer was separated using a phase separator cartridge and evaporated. The residual oil was dissolved in diethyl ether and evaporated to afford the title compound (0.776 g, 95%) as an oil that slowly solidified. NMR (300 MHz, CDC13): 0.92 (3H, t, J 7.4 Hz), 1.25 (9H, s), 1.87 - 1.79 (2H, sextet, J 7.4 Hz), 3.35 (2H, br s), 3.85 (2H, t, J 7.4 Hz), 5.41 (1H, s).
A mixture of 4,4-dimethyl-3-oxopentane nitrile (77 g, 0.62 mol) and3-fluorophenyihydrazine hydrochloride (100 g, 0.62 mol) was added to toluene (1 L) andheated to 10000 (reflux) for 24 hours. The reaction mixture was then allowed to cool to20C. The reaction mixture was then filtered, washed with toluene (2 x 250 mL), anddried in vacuo. The crude HCI salt was combined with a previous batch (performed using180 g of <strong>[2924-16-5]3-fluorophenylhydrazine hydrochloride</strong>) and partitioned between DCM (4 L) and sat. aq. NaHCO3 (4 L). The mixture was stirred until no solid remained. The DCM layer was separated off, dried (MgSO4), filtered, and concentrated in vacuo to provide the title compound as an orange solid (210 g) in 52% yield. Purity >95% by NMR and 94.4% byLCMS.
In toluene; at 100℃; for 24h;
A mixture of 4,4-dimethyl-3-oxopentane nitrile (77 g, 0.62 mol) and <strong>[2924-16-5]3-fluorophenylhydrazine hydrochloride</strong> (100 g, 0.62 mol) was added to toluene (1 L) and heated to 100 C for 24 hours, after which point the reaction was allowed to cool to 20 C.The mixture was filtered, washed with toluene (2 x 250 mL) and pulled dry. The crude HCl salt was combined with a previous batch (performed using 180 g of <strong>[2924-16-5]3-fluorophenylhydrazine hydrochloride</strong> and 234 g of <strong>[2924-16-5]3-fluorophenylhydrazine hydrochloride</strong>) and partitioned between DCM (4 L) and sat. aq. NaHCO3 (4 L). The mixture was stirred until no solid remained. The DCM layer was separated off, dried (MgSO4), filtered and concentrated in vacuoto provide the title compound as an orange solid (210 g) in 52% yield. Purity >95% (on a molar basis)by NMR and 94.4% (on a molar basis) by LCMS.
Stage #1: naphthalen-1-yl-thiourea With acetic acid; mono(N,N,N-trimethylbenzenaminium) tribromide at 25℃; for 8h;
Stage #2: With sodium hydroxide In water; ethylene glycol for 48h; Reflux; Inert atmosphere;
Stage #3: trimethylacetylacetonitrile; p-toluenesulfonyl chloride Further stages;
Synthesis of B-23
To a suspension of 5.0 g of 1-(1-naphthyl)-2-thiourea (from Wako Pure Chemical Industries, Ltd.) in 100 mL of acetic acid was added in portions 9.6 g of benzyltrimethylammonium tribromide (from Tokyo Chemical Industry Co., Ltd.), and the mixture was stirred at room temperature for 8 hours. The reaction mixture was added dropwise to a saturated aqueous sodium bicarbonate solution (1.6 L) in an ice bath, and extracted with ethyl acetate (300 mL), and the organic phase was dried over magnesium sulfate, and then filtered and concentrated to give crude B-23A (4.9 g). The resulting crude B-23A (4.9 g) was added to ethylene glycol (50 mL), and a 50% aqueous solution of sodium hydroxide (12.2 g) was added, and then the mixture was heated under reflux for 48 hours in a nitrogen atmosphere. The reaction mixture was allowed to cool, and then added to a mixture of acetic acid (40 mL) and water (120 mL) with ice-cooling, and extracted with diethyl ether (150 mL). The organic phase was dried over magnesium sulfate, and then filtered and concentrated to give crude B-23B. The entire amount of the resulting crude B-23B was mixed with pivaloyl acetonitrile (from Tokyo Chemical Industry Co., Ltd.), and the mixture was stirred at 140° C. for 6 hours. After the reaction mixture was allowed to cool, the crude product was purified by column chromatography on silica gel to give 2.1 g of an intermediate B-23C. To a mixture of B-23C (2.0 g) in THF (3 mL) were added dropwise 7.1 mL of a 2 M hydrochloric acid/THF solution, then isopentyl nitrite (from Wako Pure Chemical Industries, Ltd.) (1.0 g) with ice-cooling, and the mixture was warmed to room temperature and then stirred for 2 hours. The resulting reaction mixture was partitioned between water and ethyl acetate, and the organic layer was washed with water, then dried over magnesium sulfate, filtered, and concentrated to give a crude intermediate B-23D. (0452) To a mixture of the crude intermediate B-23D in acetone (10 mL) were added triethylamine (from Wako Pure Chemical Industries, Ltd.) (1.1 g) and p-toluenesulfonyl chloride (from Tokyo Chemical Industry Co., Ltd.) (1.35 g) with ice-cooling, and then the mixture was warmed to room temperature and stirred for 1 hour. (0453) The resulting reaction mixture was partitioned between water and ethyl acetate, and the organic phase was dried over magnesium sulfate, and then filtered and concentrated to give crude B-23. (0454) The crude B-23 was reslurried with cold methanol, and then filtered and dried to give B-23 (1.7 g). (0455) 1H-NMR spectrum of B-23 (300 MHz, CDCl3): δ=8.7-8.6 (m, 1H), 8.0-7.9 (m, 3H), 7.9-7.8 (m, 2H), 7.7-7.65 (m, 1H), 7.65-7.6 (m, 1H), 7.4 (d.2H), 2.4 (s, 3H), 1.4 (s, 9H).
To a suspension of 4-hydrazinobenzoic acid (64) (1.00 g, 5.30 mmol) in EtOH (20 mL) containing conc hydrochloric acid (0.5 mL) was added pivaloylacetonitrile (0.730 g, 5.83 mmol) and the mixture heated to reflux for 5 hr. The reaction mixture was stirred at RT for 64 hr and the solvent evaporated in vacuo. The residue was suspended in THF and an aqueous solution of LiOH (1M, 30 mL, 30 mmol) was added and the mixture was stirred at RT for 2 hr. The THF was removed by evaporation in vacuo and the resulting aqueous solution was diluted with AcOH and subjected to SCX capture and release. Fractions containing the desired compound were combined and evaporated in vacuo. The residue was dissolved in DCM and was dried (MgSO4) and evaporated in vacuo. Co-evaporation with acetonitrile in vacuo furnished 4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)benzoic acid (65) as an orange solid (1.50 g, >100% recovery): m/z 260 (M+H)+ (ES+); 258 (M-H)- (ES-).
3.2.1. General Method for the Synthesis of 2a-2i
General procedure: A solution of the corresponding substituted phenylhydrazine hydrochloride (1 equiv.) and pivaloylacetonitrile (1.2 equiv.) was stirred overnight at 80 °C in ethanol. The solution was extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered, and evaporated to dryness.
58%
With hydrogenchloride In ethanol at 130℃; for 0.5h; Microwave irradiation; Sealed tube;
General procedure B for microwave-assisted synthesis of 5-aminopyrazoles using hydrazine hydrochloride.
General procedure: A stirred solutionof the hydrazine hydrochloride (1 eq), β-ketonitrile (1 eq) and a drop of HCl (conc.) in EtOH (10-20 mL) was irradiated in a pressure-rated sealed tube (35 mL) at 130 °C for 20-30 min using a CEM Discover microwave synthesizer by moderating the initial power (200 W). After cooling in a flow of compressed air, the mixture was basified to pH 12 by the addition of an aqueous NaOH solution (10%) and extracted with EtOAc (3 x 20 mL). The organic extracts were combined, washed with brine (30 mL), dried over MgSO4 and the solvent was evaporated in vacuo.
With triethylamine In N,N-dimethyl-formamide at 90℃; for 16h;
Typical Reaction Procedure
General procedure: 1H-Pyrazol-5-amine 1 (1 equiv.), 3-oxopropanenitrile 2 (1 equiv.), benzaldehyde 3 (1 equiv.), and Et3N (2 equiv.) were stirred in DMF (1 M) at 90 °C for 16 h. The volatiles were removed under reduced pressure (or positive N2 (g) pressure). Sodium nitrite (3 equiv.) and acetic acid (134 equiv.) were added to the crude material, and the reaction mixture was stirred for 10 min. The volatiles were removed under reduced pressure (or positive N2 (g) pressure), and the crude reaction mixture was subjected to silica gel column chromatography with ethyl acetate in hexanes.
General procedure: A solution of 4,4-dimethyl-3-oxopentanenitrile (55, 3.19 g, 25.5 mmol) and ethyl hydrazineoxalate (60, 4.59 g, 30.6 mmol) inethanol (50 mL) was stirred at reflux for 18 h, cooled to room temperature andthe solvent removed under reduced pressure.The residue was diluted with methylene chloride (150 mL) and saturatedaqueous sodium bicarbonate (100 mL) was added.The organic layer was separated and the aqueous layer was furtherextracted with methylene chloride (2 ×100 mL).The combined organic layers were washed with brine (50 mL), dried (MgSO4), filtered and concentrated underreduced pressure. The resulting residuewas purified by flash column chromatography on silica gel, eluting withmethanol/methylene chloride (gradient of 1:99 to 2:98) to afford 3-(tert-butyl)-1-ethyl-1H-pyrazol-5-amine (56) as a white solid(3.15 g, 74%)
3-(Tert-butyl)-1-ethyl-1H-pyrazol-5-amine(56)
General procedure: A solution of 4,4-dimethyl-3-oxopentanenitrile (55, 3.19 g, 25.5 mmol) and ethyl hydrazineoxalate (60, 4.59 g, 30.6 mmol) inethanol (50 mL) was stirred at reflux for 18 h, cooled to room temperature andthe solvent removed under reduced pressure.The residue was diluted with methylene chloride (150 mL) and saturatedaqueous sodium bicarbonate (100 mL) was added.The organic layer was separated and the aqueous layer was furtherextracted with methylene chloride (2 ×100 mL).The combined organic layers were washed with brine (50 mL), dried (MgSO4), filtered and concentrated underreduced pressure. The resulting residuewas purified by flash column chromatography on silica gel, eluting withmethanol/methylene chloride (gradient of 1:99 to 2:98) to afford 3-(tert-butyl)-1-ethyl-1H-pyrazol-5-amine (56) as a white solid(3.15 g, 74%)
3-(tertbutyl)-1-(2-nitrophenyl)-1H-pyrazol-5-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With hydrogenchloride; In water; at 70℃; for 2h;
2NPz was prepared as described in the literature [22]. To a solution of concentrated hydrochloric acid (3.8mL) in water (33mL) were added <strong>[3034-19-3]2-nitrophenylhydrazine</strong> (2.1220g, 9.87mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.8502g, 14.80mmol). The mixture was heated at 70C for 1h. Then, additional concentrated hydrochloric acid (3.8mL) was added and the mixture was heated for 1h more. After cooling, crushed ice was added and the mixture was neutralized with concentrated ammonium hydroxide. The resulting solid was filtered under reduced pressure, washed with cold water (3×5mL) and dried at ambient temperature affording compound (2NPz) as yellow solid in 90% yield. Single crystals suitable for X-ray diffraction were grown by slow evaporation at room temperature from a solution in CH2Cl2. The synthetic procedure for 2NPz is shown in Scheme 1. Anal. Calc. for C13H16N4O2: C% 59.99; H% 6.20; N% 21.52. Found: C% 60.11; H% 6.17; N% 21.48. M.p: 378.8K; MS (70eV)m/z (%) 260 (M+, 70.69), 245 (M+ - 15, 97.96), 218 (M+ - 57, 100), 57 (15.43). IR (KappaBetar, cm-1) nuas -NH2 3396.2, nus -NH2 3207.2, nu C-H (pyrazole) 3182.13, nu C-H (aromatic) 3070.27, nuas -CH3 2969.99, nus -CH3 2865.84, deltaNuEta2 1633.49, nu -C=C 1587.21, nu -C=N 1564.06, nuas -NO2 1531.28, nus -NO2 1349.99. NMR 1H (400MHz) (CDCl3, delta in ppm) 1.30 (bs, 9H, tBu-H); 3.62 (bs, 2H, H-7 and H-8); 5.60 (s, 1H, H-11); 7.54 (td, 1H, J=7.2Hz, J=1.7Hz, H-18); 7.66 (dd, 1H, J=6.3Hz, J=1.6Hz, H-22); 7.71 (td, 1H, J=7.9Hz, J=1.3Hz, H-20); 7.95 (dd, 1H, J=8.1Hz, J=1.3Hz, H-16); NMR 13C (100MHz) (CDCl3, delta in ppm) 30.17 (tBu-C); 32.45 (C-23); 88.92 (C-10); 125.27 (C-15); 128.69 (C-17); 128.70 (C-21); 132.05 (C-13); 133.1 (C-19); 145.95 (C-14); 146.39 (C-9); 164.19 (C-12). The atoms were numbered according to Fig.1a.
With tert.-butylhydroperoxide; 2,2'-azobis(isobutyronitrile); In methanol; at 20.0℃;
General procedure: General procedure: The substrate 1 (1.0 mmol) and thiourea 2(2.0 mmol) were added to solvent (5 mL methanol) at room tem-perature. To the reaction mixture, TBHP (3.0 mmol) and AIBN(0.2 mmol) were added respectively. The reaction mixture wasstirred at room temperature (for substrates 1a-f) or reux tem-perature (for substrates 1g-r) until TLC indicated the total consumption of 1 (for substrates 1p-q, the reaction time is 24 h).The residue was treated with saturated aqueous NaHCO3 (50 mL)and then extracted with EA (30 mL 3). The organic phase waswashed with brine (50 mL 1), dried over anhydrous Na2SO4. Thesolvent was removed and the residue was puried by ash columnchromatography on silica gel (EA/PE) to afford the desired compound 3.
95%
With tert.-butylhydroperoxide; 2,2'-azobis(isobutyronitrile); In methanol; at 20.0℃; for 2.0h;
3-carbonyl-3-tert-butylpropionitrile (I-d) (125 mg)And thiourea (II) (152 mg) were added to methanol (5 mL) at room temperature.Add to reactionPeroxy tert-butyl alcohol (288 μL)And azobisisobutyronitrile (33mg),Stir at room temperature for 2 hours.After the reaction was completed, saturated aqueous sodium bicarbonate (50 mL) was added.Extract with ethyl acetate,The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product.The crude product was isolated and purified by column chromatography (ethyl acetate: petroleum ether (v/v) = 3:7).2-amino-4-tert-butyl-5-carbonitrilethiazole (III-d) (173 mg) was obtained as a white solid. Yield: 95%.
2.2.1. Synthesis of aminopyrazole
The 5-(tert-butyl)-1H-pyrazole-3-amine (1) was obtainedfollowing a previously reported procedure [13]. Thus, in a test tube,a mixture of 4,4-dimethyl-oxopentanenitrile (1.0 g, 7.9 mmol) andhydrazine monohydrate (0.443 g, 8.66 mmol) was placed. Thesolvent-free mixture was heated at 130 C until complete consumptionof the starting materials, affording a white solid in 98%yield. No further purification was requiredThe 1-(4-bromophenyl)-3-(tert-butyl)-1H-pyrazol-5-amine (4)was prepared, as described in the literature [14]. To a concentratedhydrochloric acid solution (3.8 mL) in water (33 mL) was added (4-bromophenyl)hydrazine (2.12 g, 11.41 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.85 g, 14.79 mmol). The mixture was heatedat 70 °C for 1 h, then, additional concentrated hydrochloric acid(3.8 mL) was added and the mixture was heated for one additionalhour. After cooling, crushed ice was added and the mixture wasneutralized with concentrated ammonium hydroxide. The resultingsolid was filtered under reduced pressure, washed with cold water(3 5 mL). The starting precursor 2 was obtained in 86% yield as alight brown solid. No further purification was required
Synthesis of 171 :
[3-morpholinopropyl]hydrazine dihydrochloride 170 (500mg, 2.15mmol, 1 .0eq) and pivaloyl acetonitrile (431 mg, 3.44mmol, 1 .6eq) in ethanol wad added hydrochloric acid 12 N (1 0.Oeq). The mixture was stirred at reflux for 18h. After cooling down, sodium hydrogenocarbonate solid was added until pH was around 7. The residual salts were filtrated and washed with methanol. The filtrate was purified by flash chromatography on silica gel using dichloromethane and methanol to afford expected compound 1 71 as light yellow oil (Yield: 66%, 381 mg, 66%).
66%
With hydrogenchloride In ethanol; lithium hydroxide monohydrate for 16h; Reflux;
1 Synthesis of 26: 3-(tert-butyl)-1-(2-morpholinoethyl)-1H-pyrazol-5-amine (General Procedure D)
General procedure: On a suspension of 25 (1g, 3.9mmol) and pivaloyl acetonitrile (0.49g, 3.9mmol) in 100mL EtOH was added HCl 12 N (10.0eq). The reaction mixture was refluxed for 16h. After cooling down, NaHCO3 solid added until pH was around 7 and the mixture was evaporated off then the residue was purified by column chromatography on silica gel (DCM-MeOH) to afford compound 26 (Yield: 30%, 0.3g).
66%
With hydrogenchloride In ethanol; lithium hydroxide monohydrate for 16h; Reflux;
1 Synthesis of 26: 3-(tert-butyl)-1-(2-morpholinoethyl)-1H-pyrazol-5-amine (General Procedure D)
General procedure: On a suspension of 25 (1g, 3.9mmol) and pivaloyl acetonitrile (0.49g, 3.9mmol) in 100mL EtOH was added HCl 12 N (10.0eq). The reaction mixture was refluxed for 16h. After cooling down, NaHCO3 solid added until pH was around 7 and the mixture was evaporated off then the residue was purified by column chromatography on silica gel (DCM-MeOH) to afford compound 26 (Yield: 30%, 0.3g).
3-(tert-butyl)-1-(2-morpholinoethyl)-1H-pyrazol-5-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
In ethanol for 16h; Reflux;
Synthesis of (26): 3-(tert-butyl)-1 -(2-morpholinoethyl)-1 H-pyrazol-5-amine
Suspension of hydrazine hydrochloride 25 (1 g , 3.9mmol) and 4,4-dimethyl-3-oxopentanenitrile (0.49g, 3.9mmol) in 100mL EtOH was refluxed for 16 h. After cooling the mixture was evaporated off then residue was purified by column chromatography on silica gel (DCM-MeOH) (Yield: 30%, 0.3g).
30%
With hydrogenchloride In ethanol; lithium hydroxide monohydrate for 16h; Reflux;
1 Synthesis of 26: 3-(tert-butyl)-1-(2-morpholinoethyl)-1H-pyrazol-5-amine (General Procedure D)
On a suspension of 25 (1g, 3.9mmol) and pivaloyl acetonitrile (0.49g, 3.9mmol) in 100mL EtOH was added HCl 12 N (10.0eq). The reaction mixture was refluxed for 16h. After cooling down, NaHCO3 solid added until pH was around 7 and the mixture was evaporated off then the residue was purified by column chromatography on silica gel (DCM-MeOH) to afford compound 26 (Yield: 30%, 0.3g).
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