* 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.
A mixture of 1 , 1 ,3,3-tetramethoxypropane (37 g, 226 mmol), tert-butyl-hydrazine hydrochloride (28 g, 226 mmol) and cone HCl (60 mL, 720 mmol) in EtOH (300 mL) was heated at reflux overnight. The mixture was poured into water and the resulting mixture was extracted with ether. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give 1-tert-butyl-lH-pyrazole (25 g, 89percent yield). 1H NMR (400 MHz, OMSO-Cl6): δl.n (s, 1 H), 7.38 (s, 1 H), 6.17 (s, 1 H), 1.47 (s, 9 H); MS (ESI) m/z: 125.1 [M+H]+.
89%
With hydrogenchloride In ethanol; waterReflux
A mixture of 1,1,3,3-tetramethoxypropane (3.7 g, 22.6 mmol), tert-butylhydrazinehydrochloride (2.8 g, 22.6 mmol), and conc. HCl (6 mL, 72 mmol) in EtOH (30 mL) was heated at reflux overnight. The reaction mixture was poured into water and the resulting mixture wasextracted with ether (30 mL x 3). The combined organics was washed with brine (20 mL), dried over MgSO4, and concentrated under reduced pressure to afford 1-tert-butyl-1H-pyrazole as awhite solid (2.5 g, 89percent). MS (ESI) m/z: 125 [M+H].
72%
Stage #1: With hydrogenchloride In ethanol; water at 50℃; for 2 h; Reflux; Industry scale Stage #2: With sodium hydroxide In water
To a mixture of 1 ,1 ,3,3-tetramethoxypropane (3.82kg, 23.27mol) and tert- butylhydrazine hydrochloride (2.9kg, 23.27mol) in ethanol (24.54kg), cone HCI (4.72kg ,46.55mol) was added, keeping the temperature below 50°C. The reaction mixture was then rapidly heated to reflux. After ca. 2h the reaction was sampled and analysed by NMR. Pass criteria was <3.0percent starting material remaining. On receipt of a pass result the solution is cooled, diluted with water (8.29kg) and evaporated in vacuo (T<50°C, p<-0.08MPa) until approximately all of the original ethanol was removed. The solution was basified with 10M NaOH(aq), extracted with EtOAc (1 1 .1 1 kgx2) and the organic phase washed with saturated ammonium chloride solution (4.3ml/g x 2) and brine (4.3ml/g), then evaporated to give the title compound (2.08kg, 72percentyield) as a brown liquid (GC purity 99.70percenta/a).
72%
With hydrogenchloride In ethanol; water at 50℃; for 0.2 h; Reflux; Industrial scale
Stage a) Preparation of 1-(1,1-Dimethylethyl)-1H-pyrazole (Intermediate 9) To a mixture of 1,1,3,3-tetramethoxypropane (3.82 kg, 23.27 mol) and tert-butylhydrazine hydrochloride (2.9 kg, 23.27 mol) in ethanol (24.54 kg), conc HCl (4.72 kg, 46.55 mol) was added, keeping the temperature below 50° C. The reaction mixture was then rapidly heated to reflux. After ca. 2 h the reaction was sampled and analysed by NMR. Pass criteria was <3.0percent starting material remaining. On receipt of a pass result the solution is cooled, diluted with water (8.29 kg) and evaporated in vacuo (T<50° C., p<-0.08 MPa) until approximately all of the original ethanol was removed. The solution was basified with 10M NaOH(aq), extracted with EtOAc (11.11 kg*2) and the organic phase washed with saturated ammonium chloride solution (4.3 ml/g*2) and brine (4.3 ml/g), then evaporated to give the title compound (2.08 kg, 72percent yield) as a brown liquid (GC purity 99.70percent a/a).
21.9 g
With hydrogenchloride In ethanol for 2 h; Reflux
To a stirred mixture of 34.48 g of 1,1,3,3-tetramethoxy-propane and 26.20 g tert.butyihydrazine hydrochloride in 230 mL ethanol was added 40.0 mL conc. hydrochloric acid dropwise below 50 00, then the mixture was stirred under reflux for 2 h. The reaction mixture was diluted with water. The solvent was almost removed by destillation and the aqueous residue extracted with diethylether. The combined aqueous phases were basified with iON sodium hydroxide solution and extracted with diethylether. The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield 21.90 g of 1-tert-butyl-pyrazole as oil.Analysis: HPLC-MS: R1 = 0.412 mm (method A), M+H = 125
Stage #1: With sodium hydroxide In water; toluene at 20℃; Stage #2: at 20℃; Stage #3: With acetic acid In water; toluene at 45 - 50℃; for 18 h;
Example 37 A; Synthesis of 2-(i-butyl)-4,5-dichloropyridazin-3(2H)-one (Compound 11); Solid i-butyl hydrazine hydrochloride (1 equiv) was added to a stirred solution of sodium hydroxide (0.95 equiv) dissolved in 10percent water/toluene mixture (6 vol) at ambient temperature. The resulting white suspension was cooled slightly while mucochloric acid (1 equiv) was slowly added. After completion of the addition, the reaction mixture was stirred at ambient temperature for 20-30 minutes followed by dropwise addition of acetic acid (0.95 equiv). The reaction mixture was heated to 45 - 50 °C and stirred for 18 h, until starting material was consumed, as measured by HPLC. The reaction solution was allowed to cool to ambient temperature and then was diluted with water (~7 vol) and the organic layer separated. The organic layer was cooled to 0 °C and washed with 30percent NaOH (3.6 vol), followed by 35percent HC1 (3.6 vol) and water (2 x 3.6 vol). The organic solution was concentrated under vacuum and restripped with methanol (1.5 vol) to yield compound 11 as a brown solid that was dried under vacuum at 35 °C (65-75percent yield, 100percent purity by HPLC).
Reference：
[1] Patent: WO2011/97649, 2011, A2, . Location in patent: Page/Page column 151
[2] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 3, p. 1312 - 1320
3
[ 7400-27-3 ]
[ 84956-71-8 ]
Reference：
[1] Patent: US6307047, 2001, B1,
4
[ 13952-70-0 ]
[ 7400-27-3 ]
Reference：
[1] Liebigs Annalen der Chemie, 1981, # 5, p. 943 - 966
5
[ 79371-20-3 ]
[ 7400-27-3 ]
Reference：
[1] Liebigs Annalen der Chemie, 1981, # 5, p. 943 - 966
6
[ 79371-20-3 ]
[ 4923-84-6 ]
[ 7400-27-3 ]
[ 13952-70-0 ]
Reference：
[1] Liebigs Annalen der Chemie, 1981, # 5, p. 943 - 966
7
[ 79371-16-7 ]
[ 4923-84-6 ]
[ 7400-27-3 ]
[ 13952-70-0 ]
Reference：
[1] Liebigs Annalen der Chemie, 1981, # 5, p. 943 - 966
8
[ 7400-27-3 ]
[ 94-05-3 ]
[ 112779-14-3 ]
Yield
Reaction Conditions
Operation in experiment
77%
With sodium acetate In ethanol for 16 h; Heating / reflux
Step 1. 5-Amino-1-tert-butyl-1H-pyrazole-4-carboxylic acid ethyl ester A solution containing t-butylhydrazine hydrochloride salt (10 g, 80.3 mmol), ethyl (ethoxymethylene)-cyanoacetate (13.6 g, 80.4 mmol), and anhydrous sodium acetate (8.2 g, 100 mmol) in 100 mL ethanol was stirred and refluxed for 16 hours. The solution was poured into ice-water. The separated aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed successively with water and saturated brine solution and dried with sodium sulfate. The solvent was removed in vacuo to give 5-amino-1-tert-butyl-1H-pyrazole-4-carboxylic acid ethyl ester (13 g, 77percent).
(step 1) A solution of tert-butylhydrazine monohydrochloride (13.9 g, 111.55 mmol), sodium acetate (11.44 g, 139.43 mmol) and ethyl 2-(ethoxymethylene)-2-cyanoacetate (19 g, 112.31 mmol) in ethanol (130 mL) was heated under reflux for 20 hr. Ethanol was evaporated under reduced pressure, and ethyl acetate was added to the residue. The solution was washed with aqueous sodium hydrogen carbonate solution and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 2→35percent ethyl acetate/hexane) to give ethyl 5-amino-1-tert-butyl-1H-pyrazole-4-carboxylate (24 g, 111.55 mmol, 102percent) as a pale-yellow oil. 1H-NMR(300MHz,CDCl3):δ1.33(3H, t, J=7.16Hz), 1.63(9H, s), 4.26(2H, q, J=7.03Hz), 5.25(2H,br.s.),7.57(1H, s)
Reference：
[1] Journal of Heterocyclic Chemistry, 1987, vol. 24, p. 693 - 695
11
[ 7400-27-3 ]
[ 123-06-8 ]
[ 158001-28-6 ]
Yield
Reaction Conditions
Operation in experiment
94%
Stage #1: With triethylamine In ethanol for 1 h; Stage #2: at 80℃;
To a suspension of fe/ -butylhydrazine hydrochloride (15.0 g, 120.4 mmol) in ethanol (600 ml_) was added triethylamine (16.8 ml_, 120.4 mmol). The mixture was stirred for 60 min until the hydrazine had dissolved. Ethoxymethylenemalononitrile (14.7 g, 120.4 mmol) was added in portions and the reaction mixture was heated to 80 °C and stirred at this temperature overnight. The reaction mixture was concentrated to dryness and the obtained residue was taken up in EtOAc. The organic layer was washed with water, dried over Na2S04, filtered and concentrated under reduced pressure. The solid was then recrystallized in DCM to afford 5-amino-1 -fe/?-butyl-pyrazole-4-carbonitrile (18.6 g, 1 13.4 mmol, 94percent yield) as a light yellow solid. LC-MS (ES+, method 1): 1 .36 min, m/z 165.1 [M+H]+
83%
With triethylamine In ethanol for 3 h; Reflux
In tert-butylhydrazine hydrochloride (8.67 g, 69.6 mmol)Was added triethylamine (9.7 mL, 69.6 mmol)After adding anhydrous ethanol (460 mL), the mixture was stirred and dissolved at room temperature,Ethoxymethylenemalononitrile (8.5 g, 69.6 mmol) was added in small portions.After heating the solution to reflux for 3 hours,After cooling, the solvent was evaporated to give an orange solid.And extracted with ethyl acetate (0.5 L) and water (0.25 L)After drying by adding magnesium sulfate,The organic layer was evaporated to give an orange-yellow solid.The resulting solid was continuously washed with a 10percent ethyl acetate in cyclohexane solution to give a crystalline solid5-amino-1-tert-butyl hydrogen - pyrazol-4-cyano 9.54g(Yield: 83percent).
64.4%
With triethylamine In ethanol for 3 h; Heating / reflux
A mixture of t-butylhydrazine hydrochloride (4.67 g, 53 mmol) and triethylamine (5.35 g, 53 mmol) in anhydrous ethanol (250 ml) was stirred and ethoxymethylene malononitrile (6.47 g, 53 mmol) was slowly added in portions. The mixture was heated at reflux for 3 hr. The solvent was removed in vacuo and the product was crystallized from ethyl acetate -hexane followed by ether to afford the title compound as light pale brown crystals (5.6 g, 64.4 percent); LC/MS, API-ES, Neg, (M-H)", 163.0.
Reference：
[1] MedChemComm, 2017, vol. 8, # 3, p. 640 - 646
[2] Patent: WO2017/46604, 2017, A1, . Location in patent: Paragraph 00228
[3] Organic Letters, 2012, vol. 14, # 15, p. 3906 - 3908
[4] Patent: CN106008527, 2016, A, . Location in patent: Paragraph 0048; 0049; 0050; 0051
[5] European Journal of Organic Chemistry, 2008, # 19, p. 3377 - 3381
[6] Patent: WO2007/126841, 2007, A2, . Location in patent: Page/Page column 73
[7] Patent: WO2009/62118, 2009, A2, . Location in patent: Page/Page column 170
[8] Patent: WO2017/161344, 2017, A1, . Location in patent: Paragraph 0813-814
[9] Journal of Medicinal Chemistry, 2017, vol. 60, # 24, p. 9976 - 9989
With potassium hydroxide; at 20℃; for 3h;Inert atmosphere;
Acetone tert-butyl hydrazine (E) tert-Butyl hydrazine hydrochloride (25.80 g, 207.1 mmol), potassium hydroxide (26.10 g, 465.2 mmol) and acetone (26.10 g, 449.4 mmol) were mixed together and stirred at room temperature under nitrogen for 3 hours. Upon completion, the supernatant liquid was decanted into another flask, the remaining liquid was carefully removed under reduced pressure, and the residue was purified by distillation at 60 C. (76.0 mm Hg) to afford (E) as clear oil in 71% yield. 1H NMR (500 MHz, CDCl3): 1.91 (s, 3H), 1.70 (s, 3H), 1.16 (m, 9H).
With triethylamine; In acetone;Reflux; Heating;
tert-Butyl hydrazine hydrochloride (1 mol, 1.0 eq)Stir with acetone (100mL) at room temperature,Triethylamine (1.5 mmol, 1.5 eq) was added dropwiseAcetone (suitable) solution,After the completion of the dropwise addition, the reaction was refluxed for 6-8 h.cool down,Add an appropriate amount of anhydrous magnesium sulfate,Heating and continuing to reflux for 2-3 hours,cool down,filter,Desolvent,A light orange liquid is obtained.
EXAMPLE 1 Preparation of N'-t-butyl-N-benzoylhydrazine To a stirred suspension of t-butylhydrazine hydrochloride (1.24 g, 10 mmol) in toluene (30 ml) at room temperature was added dropwise a 50percent aqueous solution of sodium hydroxide (0.8 g, 10 mmole). After 15 min., the reaction mixture was cooled to 5° C. and a solution of benzoyl chloride (1.42 g, 10 mmol) in toluene (5 ml) and a solution of 50percent aqueous sodium hydroxide (0.8 g, 10 mmol) were added dropwise simultaneously from separate addition funnels while maintaining the temperature at or below 10°. Following the addition, the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was diluted with toluene washed with water. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent removed under vacuum to afford a yellow oil which slowly solidified on standing. The product was recrystallized from ethyl ether:hexane to afford white crystals.
With sodium acetate; In ethanol; for 16h;Heating / reflux;
Step 1. 5-Amino-1-tert-butyl-1H-pyrazole-4-carboxylic acid ethyl ester A solution containing t-butylhydrazine hydrochloride salt (10 g, 80.3 mmol), ethyl (ethoxymethylene)-cyanoacetate (13.6 g, 80.4 mmol), and anhydrous sodium acetate (8.2 g, 100 mmol) in 100 mL ethanol was stirred and refluxed for 16 hours. The solution was poured into ice-water. The separated aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed successively with water and saturated brine solution and dried with sodium sulfate. The solvent was removed in vacuo to give 5-amino-1-tert-butyl-1H-pyrazole-4-carboxylic acid ethyl ester (13 g, 77%).
Step 2: 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylic acid methyl ester A solution of 2-dimethylaminomethylene-3-oxo-butyric acid methyl ester (7.43 g, 43.40 mmol) in absolute ethanol (70 mL) was treated with tert-butylhydrazine hydrochloride (5.52 g, 44.29 mmol) and sodium acetate (4.42 g, 53.88 mmol). The resulting mixture was heated to 90° C. for 18 h. At this time, the reaction was cooled to 25° C. The reaction was poured onto ice using dichloromethane to assist the transfer (50 mL). The mixture was transferred to a separatory funnel at which time the layers were shaken and separated. The aqueous layer was further extracted with dichloromethane (1*50 mL). The combined organics were washed with a saturated aqueous sodium bicarbonate solution (1*50 mL), water (1*50 mL) and a saturated aqueous sodium chloride solution (1*50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. ISCO CombiFlash (120 g column; 0-10percent ethyl acetate/hexanes) afforded 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylic acid methyl ester (6.04 g, 71percent) as a yellow oil.
1-tert-butyl-5-(5-methylisoxazol-3-yl)-1H-pyrazole-4-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With sodium acetate; In ethanol; at 90℃; for 18h;
Step 2: 1-tert-butyl-5-(5-methyl-isoxazol-3-yl)-1H-pyrazole-4-carboxylic acid methyl ester A solution of 3-dimethylamino-2-(5-methyl-isoxazole-3-carbonyl)-acrylic acid ethyl ester (27.53 mmol) in absolute ethanol (41.7 mL) was treated with <strong>[7400-27-3]tertbutylhydrazine hydrochloride</strong> (3.57 g, 28.63 mmol) and sodium acetate (2.80 g, 34.13 mmol). The resulting mixture was heated to 90° C. for 18 h. At this time, the reaction was cooled to 25° C. The reaction was diluted with water (200 mL) and was then extracted with dichloromethane (3*150 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 1-tert-butyl-5-(5-methyl-isoxazol-3-yl)-1H-pyrazole-4-carboxylic acid methyl ester (7.37 g, 96percent) as a black solid. The material was used without further purification.
Formyl-3-oxo-propionic acid ethyl ester (75.85 g, 525.6 mmol) was dissolved in ethanol (1 L) at room temp. Tert-butylhydrazine hydrochloride (65.5 g, 525.6 mmol) was added at room temp and the reaction temperature gradually increased to 32° C. The flask was then placed in an ice-bath to cool it back to 20° C. It took ca. 1 h for t-butylhydrazine to fully dissolve. The solution was stirred at room temp. for 3 h. The reaction mixture was cooled in an ice-bath. Sodium hydroxide (4N, 152.4 g) was added to neutralize the hydrochloric acid. Most of the ethanol was then removed in vacuo and methanol (300 ml) was added followed by additional sodium hydroxide (4N, 304.8 g, 1.05 mol). The internal temperature gradually rose to 32° C. The reaction flask was then placed in a water bath to cool it back to room temp. and the reaction was allowed to stir at room temp. for 18 h. Methanol (300 ml) was then removed in vacuo with the water bath temperature kept below 30° C. The reaction mixture was then cooled to 0° C. and hydrochloric acid (6N, 190 ml) was added slowly to keep internal temperature below 15° C. The solution was adjusted to pH=2. The resulting suspension was allowed to stir in the ice-bath for 2 h, and the solid was filtered. After drying at 60° C. in vacuo for 2.5 days, 1-tert-butyl-1H-pyrazole-4-carboxylic acid (56.06 g) of off-white solid was collected. The mother liquor was extracted 3 times with dichloromethane (200 ml.x.3). The combined organic layer was washed once with brine (100 ml) and dried over magnesium sulfate. After concentrating in vacuo and drying, 16.5 g of yellowish solid was collected. The crude material was crystallized in hot iso-propyl acetate (25 ml) and heptane (25 ml). After cooling to room temp, the solid was filtered off and the cake was washed with mixed solvent of isopropyl acetate and heptane (1/1 (v/v, 14 ml) and dried in oven at 60° C. in vacuo for 5 h. A second crop of 1-tert-butyl-1H-pyrazole-4-carboxylic acid (7 g) was collected as a white solid.
With triethylamine; In ethanol; water; at 78.0℃; for 3.0h;
Dissolve tert-butylhydrazine hydrochloride (8 g, 64.20 mmol) and triethylamine (6.50 g, 64.20 mmol) in 500 mL of absolute ethanol. Then, 2-ethoxymethylenemalononitrile (7.83 g, 64.20 mmol) was slowly added dropwise to the reaction flask with stirring. It was heated to reflux at 78 C. After about 3 h, the reaction was monitored by TLC (developer: PE / EtOAc = 1: 1). After the reaction solution was cooled to room temperature, the solvent was concentrated under reduced pressure to remove the solvent, and 100 mL of water and CH 2 Cl 2 (300 mL × 3) were added for extraction. The organic phases were combined, dried by adding an appropriate amount of anhydrous sodium sulfate, and concentrated to obtain an orange-yellow viscous solid. The obtained crude product was dissolved in 60 mL of an ethyl acetate-n-hexane (1: 9) mixed solution, sonicated for about 5 min, and allowed to stand. Observed that a large number of crystal forms precipitated, and filtered (washed 3 times with the ethyl acetate-n-hexane mixed solution). Drying gave 10.11 g of 1-tert-butyl-5-amino-1H-pyrazole-4-carbonitrile as an orange solid product, yield: 96%.
96%
With triethylamine; In ethanol; at 78.0℃; for 3.0h;
tert-butylhydrazine hydrochloride (8g, 64.20mmol) and triethylamine (6.50g, 64.20mmol) In 500 mL of absolute ethanol, 2-ethoxymethylenemalononitrile (7.83 g, 64.20 mmol) was slowly added dropwise to the reaction flask with stirring.It was heated to reflux at 78 C. After about 3 h, the reaction was monitored by TLC (developer: PE / EtOAc = 1: 1).After the reaction solution was cooled to room temperature, the solvent was concentrated under reduced pressure to remove the solvent, and 100 mL of water and CH2Cl2(300 mL × 3) were added for extraction. The organic phases were combined, dried by adding an appropriate amount of anhydrous sodium sulfate, and concentrated to obtain an orange-yellow viscous solid.The obtained crude product was dissolved in 60 mL of an ethyl acetate-n-hexane (1: 9) mixed solution, sonicated for about 5 min, and allowed to stand. Observed that a large number of crystal forms precipitated, and filtered (washed 3 times with the ethyl acetate-n-hexane mixed solution) Drying gave 10.11 g of 1-tert-butyl-5-amino-1H-pyrazole-4-carbonitrile as an orange solid product, yield: 96%.
94%
To a suspension of fe/ -butylhydrazine hydrochloride (15.0 g, 120.4 mmol) in ethanol (600 ml_) was added triethylamine (16.8 ml_, 120.4 mmol). The mixture was stirred for 60 min until the hydrazine had dissolved. Ethoxymethylenemalononitrile (14.7 g, 120.4 mmol) was added in portions and the reaction mixture was heated to 80 C and stirred at this temperature overnight. The reaction mixture was concentrated to dryness and the obtained residue was taken up in EtOAc. The organic layer was washed with water, dried over Na2S04, filtered and concentrated under reduced pressure. The solid was then recrystallized in DCM to afford 5-amino-1 -fe/?-butyl-pyrazole-4-carbonitrile (18.6 g, 1 13.4 mmol, 94% yield) as a light yellow solid. LC-MS (ES+, method 1): 1 .36 min, m/z 165.1 [M+H]+
83%
With triethylamine; In ethanol; for 3.0h;Reflux;
In tert-butylhydrazine hydrochloride (8.67 g, 69.6 mmol)Was added triethylamine (9.7 mL, 69.6 mmol)After adding anhydrous ethanol (460 mL), the mixture was stirred and dissolved at room temperature,Ethoxymethylenemalononitrile (8.5 g, 69.6 mmol) was added in small portions.After heating the solution to reflux for 3 hours,After cooling, the solvent was evaporated to give an orange solid.And extracted with ethyl acetate (0.5 L) and water (0.25 L)After drying by adding magnesium sulfate,The organic layer was evaporated to give an orange-yellow solid.The resulting solid was continuously washed with a 10% ethyl acetate in cyclohexane solution to give a crystalline solid5-amino-1-tert-butyl hydrogen - pyrazol-4-cyano 9.54g(Yield: 83%).
83%
With triethylamine; In ethanol; at 20.0℃; for 3.0h;Reflux;
Triethylamine (9.7mL, 69.6mmol) was added to tert-butylhydrazine hydrochloride (8.67g, 69.6mmol) After adding absolute ethanol (460mL) and stirring at room temperature to dissolve, Ethoxymethylenemalononitrile (8.5 g, 69.6 mmol) was added in small portions, the solution was heated to reflux for 3 hours, and then the solvent was evaporated in vacuo to obtain a crude orange product. It was extracted with a mixed solution of ethyl acetate (0.5 L) and water (0.25 L), dried over anhydrous magnesium sulfate, and the organic layer was evaporated to obtain an orange solid. Continue to wash the obtained solid with a cyclohexane solution containing 10% ethyl acetate to obtain crystalline solid 5-amino-1-tert-butyl 1hydro-pyrazole-4-cyano 9.54g (yield 83% ).
64.4%
With triethylamine; In ethanol; for 3.0h;Heating / reflux;
A mixture of t-butylhydrazine hydrochloride (4.67 g, 53 mmol) and triethylamine (5.35 g, 53 mmol) in anhydrous ethanol (250 ml) was stirred and ethoxymethylene malononitrile (6.47 g, 53 mmol) was slowly added in portions. The mixture was heated at reflux for 3 hr. The solvent was removed in vacuo and the product was crystallized from ethyl acetate -hexane followed by ether to afford the title compound as light pale brown crystals (5.6 g, 64.4 %); LC/MS, API-ES, Neg, (M-H)", 163.0.
With triethylamine; In ethanol; for 3.0h;Heating / reflux;
A mixture of t-butylhydrazine hydrochloride (4.67 g, 53 mmol) and triethylamine (5.35 g, 53 mmol) in anhydrous ethanol (250 ml) was stirred and ethoxymethylene malononitrile (6.47 g, 53 mmol) was slowly added in portions. The mixture was heated at reflux for 3 hr. The solvent was removed in vacuo and the product was crystallized from ethyl acetate - hexane followed by ether to afford 5-amino-l-tert-butyl-lH-pyrazole-4-carbonitrile as light pale brown crystals (5.6 g, 34.1 mmol); LC/MS, API-ES, Neg, (M-H)", 163.0.
With triethylamine; In ethanol; at 82.0℃; for 3.0h;Inert atmosphere;
[0814] Example 1: 5-amino-1-(tert-butyl)-1H-pyrazole-4-carbonitrile (I1): . In a 250mL flame-dried argon purged round bottom flask, triethylamine (1.78g, 17.7mmol), and t- butyl hydrazine hydrochloride (1.56g, 12.5mmol) are dissolved in anhydrous ethanol (85mL). Ethoxymethylenemalononitrile (1.98g, 17.7mmol) is added slowly and reaction mixture is brought to reflux at 82C for 3 hours. The solvent is removed in vacuo and 10% ethyl acetate / hexane is added (5mL) and the mixture is sonicated (or simply utilize recrystallization from 10% ethyl acetate / hexane). The resulting crystalline solid is filtered, and washed with ether to yield I1. LC-MS (ES+) calcd for C8H12N4 (M+H)+ 165.11, found 165.05.
Synthesis of 1-tert-butyl-1H-pyrazol-5-amine To 600 ml of ethanol were successively added 59.94 g of tert-butylhydrazine hydrochloride, 79.3 g of sodium acetate and 50 ml of 2-chloroacrylonitrile at room temperature, followed by stirring the reaction mixture at 80 C. for 12 hours. After removing the solvent in vacuo, water was added to the residue. The mixture was neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The obtained ethyl acetate solution was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The obtained residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=2/1-1/2) to give the title compound as a pale yellow oil.
With hydrogenchloride; In ethanol;Heating / reflux;
A mixture of 1 , 1 ,3,3-tetramethoxypropane (37 g, 226 mmol), tert-butyl-hydrazine hydrochloride (28 g, 226 mmol) and cone HCl (60 mL, 720 mmol) in EtOH (300 mL) was heated at reflux overnight. The mixture was poured into water and the resulting mixture was extracted with ether. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give 1-tert-butyl-lH-pyrazole (25 g, 89% yield). 1H NMR (400 MHz, OMSO-Cl6): deltal.n (s, 1 H), 7.38 (s, 1 H), 6.17 (s, 1 H), 1.47 (s, 9 H); MS (ESI) m/z: 125.1 [M+H]+.
89%
With hydrogenchloride; In ethanol; water;Reflux;
A mixture of 1,1,3,3-tetramethoxypropane (3.7 g, 22.6 mmol), tert-butylhydrazinehydrochloride (2.8 g, 22.6 mmol), and conc. HCl (6 mL, 72 mmol) in EtOH (30 mL) was heated at reflux overnight. The reaction mixture was poured into water and the resulting mixture wasextracted with ether (30 mL x 3). The combined organics was washed with brine (20 mL), dried over MgSO4, and concentrated under reduced pressure to afford 1-tert-butyl-1H-pyrazole as awhite solid (2.5 g, 89%). MS (ESI) m/z: 125 [M+H].
72%
To a mixture of 1 ,1 ,3,3-tetramethoxypropane (3.82kg, 23.27mol) and tert- butylhydrazine hydrochloride (2.9kg, 23.27mol) in ethanol (24.54kg), cone HCI (4.72kg ,46.55mol) was added, keeping the temperature below 50C. The reaction mixture was then rapidly heated to reflux. After ca. 2h the reaction was sampled and analysed by NMR. Pass criteria was <3.0% starting material remaining. On receipt of a pass result the solution is cooled, diluted with water (8.29kg) and evaporated in vacuo (T<50C, p<-0.08MPa) until approximately all of the original ethanol was removed. The solution was basified with 10M NaOH(aq), extracted with EtOAc (1 1 .1 1 kgx2) and the organic phase washed with saturated ammonium chloride solution (4.3ml/g x 2) and brine (4.3ml/g), then evaporated to give the title compound (2.08kg, 72%yield) as a brown liquid (GC purity 99.70%a/a).
72%
With hydrogenchloride; In ethanol; water; at 50℃; for 0.2h;Reflux; Industrial scale;
Stage a) Preparation of 1-(1,1-Dimethylethyl)-1H-pyrazole (Intermediate 9) To a mixture of 1,1,3,3-tetramethoxypropane (3.82 kg, 23.27 mol) and tert-butylhydrazine hydrochloride (2.9 kg, 23.27 mol) in ethanol (24.54 kg), conc HCl (4.72 kg, 46.55 mol) was added, keeping the temperature below 50 C. The reaction mixture was then rapidly heated to reflux. After ca. 2 h the reaction was sampled and analysed by NMR. Pass criteria was <3.0% starting material remaining. On receipt of a pass result the solution is cooled, diluted with water (8.29 kg) and evaporated in vacuo (T<50 C., p<-0.08 MPa) until approximately all of the original ethanol was removed. The solution was basified with 10M NaOH(aq), extracted with EtOAc (11.11 kg*2) and the organic phase washed with saturated ammonium chloride solution (4.3 ml/g*2) and brine (4.3 ml/g), then evaporated to give the title compound (2.08 kg, 72% yield) as a brown liquid (GC purity 99.70% a/a).
21.9 g
With hydrogenchloride; In ethanol; for 2.0h;Reflux;
To a stirred mixture of 34.48 g of 1,1,3,3-tetramethoxy-propane and 26.20 g tert.butyihydrazine hydrochloride in 230 mL ethanol was added 40.0 mL conc. hydrochloric acid dropwise below 50 00, then the mixture was stirred under reflux for 2 h. The reaction mixture was diluted with water. The solvent was almost removed by destillation and the aqueous residue extracted with diethylether. The combined aqueous phases were basified with iON sodium hydroxide solution and extracted with diethylether. The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield 21.90 g of 1-tert-butyl-pyrazole as oil.Analysis: HPLC-MS: R1 = 0.412 mm (method A), M+H = 125
The beta-ketoester (110) (0.90 g, 3.31 mmol) was dissolved in dimethylformamide dimethylacetal (3 mL), and was heated to 50° C. for 15 min. The reaction mix was cooled to room temperature and concentrated. The resulting residue was dissolved in EtOH (15 mL) and tert-butylhydrazine hydrochloride (0.49 g, 4.97 mmol) was added followed by three drops of concentrated HCl. The reaction mix was stirred at room temperature for 10 minutes, and then was microwaved at 150° C. for 25 min. The reaction mixture was concentrated. The resulting residue was dissolved in EtOAc (25 mL) and was washed with H2O (10 mL) and saturated aqueous NaHCO3 (10 mL). The organic layer was dried with MgSO4, filtered and concentrated The resulting residue was purified by flash chromatography (20percent EtOAc in hexanes) to afford (111) (1.47 g, 60percent) MS (ES) m/z 351.9,353.9 (M+H)+.
With triethylamine; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide;
Reference Example 37 4-(2-t-Butylhydrazino)-2-chloro-7-methylthieno[3,2-d] pyrimidine To 6 ml of a solution of 438 mg (2.0 mol) of 2,4-dichloro-7-metylthieno[3,2-d]pyrimidine and 445 mg (4.4 mmol) of triethylamine in DMF was added 249 mg (2.0 mmol) of t-butylhydrazine hydrochloride under ice cooling. The reaction mixture was stirred at the same temperature for one hour and then allowed to resume room temperature, followed by stirring for further 16 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml*3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1:2) to give 314 mg (yield: 58.0%) of the title compound. NMR (delta, CDCl3): 1.18 (9H, s), 2.41 (3H, s), 3.62 (1H, br), 7.00 (1H, br), 7.46 (1H, s)
With sodium hydroxide; In petroleum ether (80 - 110 C); water; xylene; at 10 - 80℃;pH 9.0 - 9.5;
In einem Planschliffbecher werden in 230,0 g Wasser 81,3 g tert.-Butylhydrazin-Hydrochlorid geloest. Durch Zudosieren von 55,8 g Natronlauge (w = 30 percent) wird ein pH-Wert von 9,2 eingestellt. Man gibt zur Loesung 150,0 g Spezialbenzin 80/110 (Siedebereich 80-110°C) zu und kuehlt das Gemisch auf 15°C ab. Jetzt werden bei 15-20°C die unter Beispiel 8 hergestellte xylolische 3-Methoxy-2-methylbenzoylchlorid-Loesung und Natronlauge simultan so eindosiert, dass der pH-Wert im Bereich von 9,0-9,5 bleibt. Es werden in 1,5 h 180,0 g xylolische MMBC-Loesung (w = 30 percent) und 97,3 g Natronlauge (w = 30 percent) zudosiert. Die Pumpe und die Zuleitungen werden mit 43,0 g Xylol gespuelt, dieses Xylol wird zur Reaktionsmischung zugegeben. Nach Dosierende wird noch eine Stunde bei 10-15°C nachgeruehrt. Danach wird die Reaktionsmischung in 45 min auf 40°C erwaermt und bei dieser Temperatur 2 h zur Vervollstaendigung der Reaktion geruehrt. Die Suspension wird auf 70°C aufgeheizt, wobei sich der Feststoff vollstaendig in der organischen Phase loest. Die Wasserphase wird abgetrennt und verworfen. Die organische Phase wird mit 200,0 g VE-Wasser gewaschen, das Waschwasser wird ebenfalls verworfen. Zur organischen Phase werden 2,0 g Aktivkohle zugegeben, die Mischung auf 80°C aufgeheizt, und ueber ein Papierfilter filtriert. Der Filterkuchen wird mit 43,0 g Xylol nachgewaschen, die Filtrate werden vereinigt und weiterverarbeitet. Zur geklaerten organische Phase gibt man bei 60-80°C 300,0 g Spezialbenzin 80/110 und kuehlt innerhalb von 6 h auf 5°C ab. Bei ca. 38-40°C beginnt das Produkt auszufallen. Das ausgefaellte Produkt wird abgesaugt und mit Spezialbenzin 80/110 nachgewaschen. Der Niederschlag wird im Vakuumtrockenschrank bei 200 mbar 20 h bei 60°C getrocknet. Man erhaelt 109,2 g 3-Methoxy-2-methylbenzoesaeure-tert.butylhydrazid (Gehalt 95,4 percent, im HPLC eine weitere Komponente erkennbar). Das entspricht einer Ausbeute bezogen auf 3-Methoxy-2-methylbenzoesaeure von 83,2 percent d.Th.
With sodium hydroxide; In dichloromethane; water;
EXAMPLE 8 Preparation of N-(3-Methoxy-2-Methylbenzoyl)-N'-tert-Butylhydrazine from Product of EXAMPLE 5 To a stirred suspension of tert-butylhydrazine hydrochloride (397 g, 3.27 mole) in methylene chloride (2 L) at 0° C., was added sodium hydroxide (50percent aqueous, 260 g) diluted with water (400 mL). Following this, 3-methoxy-2-methylbenzoyl chloride (140 g, 0.78 mole) in methylene chloride (1 L) and sodium hydroxide (50percent aqueous, 80 g) dilutect with water (400 mL) were added concurrently at -20° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and after additional 30 minutes, the organic layer was washed with water (4*500 mL), dried over magnesium sulfate and stripped to yield N-(3-methoxy-2-methylbenzoyl)-N'-tert-butylhydrazine (177 g). 1 H-NMR (CDCl3) deltappm 1.19 (s, 9H, t-Bu), 2.29 (s, 3H, CH3), 3.87 (s, 3H, OCH3), 6.90 (d, 1H, C-4 or 6), 6.95 (d, 1H, C-4 or C6) 7.19 (dd, 1H, C-5).
With sodium hydroxide; In water; xylene; gasoline; at 10 - 40℃; for 4.25h;pH 9.0 - 9.5;
In a flat-flanged vessel, 81.3 g of tert-butylhydrazine hydrochloride are dissolved in 230.0 g of water. A pH of 9.2 is set by metering in 55.8 g of sodium hydroxide solution (w=30percent). 150.0 g of {fraction (80/110)} special-boiling-point gasoline (boiling range 80-110° C.) are added and the mixture is cooled to 15° C. The xylenic 3-methoxy-2-methylbenzoyl chloride solution prepared under Example 1 and sodium hydroxide solution are now simultaneously metered in at 15-20° C. in such a way that the pH remains within the range of 9.0-9.5. 180.0 g of xylenic MMBC solution (w=30percent) and 97.3 g of sodium hydroxide solution (w=30percent) are metered in within 1.5 h. The pump and the feeds are flushed with 43.0 g of xylene, and this xylene is added to the reaction mixture. On completion of metering, stirring is continued at 10-15° C. for another hour. Afterwards, the reaction mixture is heated to 40° C. within 45 min and stirred at this temperature for 2 h to complete the reaction. [0113] The suspension is heated to 70° C., and the solid dissolves completely in the organic phase. The aqueous phase is removed and discarded. The organic phase is washed with 200.0 g of demineralized water, and the washing water is likewise discarded. [0114] 2.0 g of activated carbon are added to the organic phase, and the mixture is heated to 80° C. and filtered through a filter paper. The filter cake is washed with 43.0 g of xylene, and the filtrates are combined and processed further. [0115] 300.0 g of {fraction (80/110)} special-boiling-point gasoline are added to the clarified organic phase at 60-80° C. and the mixture is cooled to 5° C. within 6 h. At approx. 38-40° C., the product begins to precipitate out. The precipitated product is filtered off with suction and washed with {fraction (80/110)} special-boiling-point gasoline. The precipitate is dried at 60° C. and 200 mbar for 20 h in a vacuum drying cabinet. 109.2 g of 3-methoxy-2-methylbenzoic tert-butylhydrazide (purity 95.4percent, one further component visible in HPLC) are obtained. This corresponds to a yield based on 3-methoxy-2-methylbenzoic acid of 83.2percent of theory.
With hydrogenchloride; In methanol; water; at 60 - 62℃; for 3h;
Example 12 (Synthesis of 5-amino-1-t-butyl-4-nitrosopyrazole) To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged, 2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 96.9percent by weight synthesised in the same manner as in Example 1, 2.70 g (21 mmol) of t-butylhydrazine hydrochloride with a purity of 97percent by weight, 1.4 ml of water, 6 ml of methanol and 1.3 ml (15 mmol) of conc. hydrochloric acid, and the mixture was reacted at 60 to 62°C for 3 hours.. After completion of the reaction, 5 ml of water was added to the mixture and the mixture was cooled up to 10°C. Then, 2.3 ml (37.9 mmol) of 28percent by weight aqueous ammonia was gradually added dropwise to the mixture, and the resulting mixture was stirred for 30 minutes while maintaining the liquid temperature to 5°C or lower.. Precipitated crystals were collected by filtration, and then, the crystals were washed with 1.2 ml of cold water and 1.2 ml of cold methanol, and dried under reduced pressure to obtain 1.93 g of 5-amino-1-t-butyl-4-nitrosopyrazole (Isolation yield: 55.2percent) as reddish orange solid with a purity of 96.2percent by weight (absolute calibration curve method by high performance liquid chromatography). Incidentally, physical properties of the 5-amino-1-t-butyl-4-nitrosopyrazole are as mentioned below.1H-NMR (DMSO-d6, delta (ppm)); 1.53 (7.2H, s), 1.58 (1.8H, s), 6.99 (0.2H, s), 7.80 to 8.30 (2H, br), 8.48 (0.8H, s) IR (KBr method, cm-1); 3345, 3160, 2983, 1632, 1524, 1478, 1238, 1079, 835, 607
With triethylamine; In tetrahydrofuran; at 20 - 64℃; for 0.75h;Heating;
Example 108 Step A: (108A) A suspension of 2-amino-4,6-dichloro-pyrimidine-5-carboxaldehyde (300 mg, 1.56 mmol) and tert-butylhydrazine hydrochloride (390 mg, 3.13 mmol) in THF (15 ML) and triethyl amine (0.44 mL, 3.13 mmol) was stirred at rt for 5 min and then heated to 64C for 40 min. The reaction mixture was concentrated and diluted with water at 0C. The solid was filtered, washed with water and dried in vacuo over P205 to obtain the title compound 108A (240 mg, 68% yield) as a yellow solid. HPLC retention time: 2.11 min ; LC/MS : 226.10 (M+H) +.
With potassium carbonate; In water; ethyl acetate; at 20℃; for 18h;
To a round bottom flask equipped with magnetic stirring was added ethyl acetate (5 mL) and 25 wt percent aqueous potassium carbonate solution (2.96 g, 5.35 mmol). To this was added t-butylhydrazine hydrochloride (0.33 g, 2.68 mmol) followed by 3-(tert-butyldimethylsilyloxymethyl)-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid pentafluorophenyl ester (0.90 g, 1.78 mmol) dissolved in ethyl acetate (4 mL). This mixture was stirred at room temperature for 18 hours. The phases were separated and the organic phase washed once with water, once with 10percent NaOH (aq), once with 1 N HCl, and once with saturated aqueous sodium chloride. The solution was dried over magnesium sulfate, filtered, and evaporated to give a white solid. This material was triturated with hexane to give a white solid, 3-(tert-butyl-dimethyl-silanyloxymethyl)-5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid N'-tert-butyl-hydrazide, (0.50 g, 1.22 mmol) in 69percent yield. 1H-NMR (300 MHz, CD3COCD3) delta (ppm): 0.12 (s, 6H), 0.92 (s, 9H), 1.53 (s, 9H), 2.32 (s, 3H), 3.97 (m, 2H), 4.14 (m, 1H), 4.28 (m, 1H), 4.43 (m, 1H), 6.79 (d, 1H), 7.22 (d, 1H); TLC Rf=0.43 (1:1 ethyl acetate:hexane).
To a suspension of 1-tert-butylhydrazine hydrochloride (5.0 g, 40 mmol) in ether (200 mL) was added TEA (5.6 mL, 40 mmol) and 4-fluorobenzaldehyde (5.0 g, 40 mmol). After stirring at RT for 30 min, MgSO4 (5.8 g, 48 mmol) was added. The resulting reaction mixture was stirred at RT for 2 days and filtered. The filtrate was evaporated under reduced pressure to afford 7.0 g (90percent) of 56b which was taken directly into the next step.
90%
EXAMPLE 28 1-tert-Butyl-4-(1,1-dioxo-1H-1lambda6-benzo[d]isothiazol-3-yl)-2-(4-fluoro-benzyl)-5-hydroxy-1,2-dihydro-pyrazol-3-one (III-2, SCHEME 9) step 1-To a suspension of 1-tert-butylhydrazine hydrochloride (5.0 g, 40 mmol) in ether (200 mL) was added TEA (5.6 mL, 40 mmol) and 4-fluorobenzaldehyde (5.0 g, 40 mmol). After stirring at room temperature for 30 min, MgSO4 (5.8 g, 48 mmol) was added. The resulting reaction mixture was stirred at RT for 2 d and filtered. The filtrate was evaporated under reduced pressure which afforded 7.0 g (90percent) of 60a which was used in step 2 without additional purification.
2-(tert-Butyl)-4,5-dichloro-3(2H)-pyridazinone A solution of mucochloric acid (33.8 g, 200 mmol) and tert.-butylhydrazine hydrochloride (24.9 g, 200 mmol) in methanol (400 mL) was stirred at reflux overnight. Methanol was removed in vacuo and the residue was partitioned between ether and water. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, 100% hexanes). Product-containing fractions were combined and the title compound was crystallized from ether/hexanes (yield: 10.0 g, 22.6%). mp 63-64 C. 1H NMR (300 MHz, CDCl3) delta 1.65 (s, 9H), 7.73 (s, 1H). MS (DCI/NH3) m/z 221 (M+H)+, 238 (M+NH4)+.
1C. Preparation of compound 1-5 (L = tert-butyl): tert-Butyl-hydrazine hydrochloride (0.5 g, 4.0 mmol) and di-tert-butyl dicarbonate (BOC2O, 1.0 g, 4.4 mmol) were dissolved in 10 ml dioxane followed by the addition of 10 ml IN NaOH aqueous solution. The reaction mixture was stirred at room temperature for 1O h. The reaction was quenched with 10 ml saturated NH4C1 aqueous solution and extracted with dichloromethane. The organic phase was dried over anhydrous Na2SO4, filtered, and then concentrated in vacuo to afford N'-tert-Butyl- hydrazinecarboxylic acid tert-butyl ester (0.6g, 80percent). 1H-NMR (500 MHz, CD3Cl): delta 5.88 (IH, br), 3.77 (IH, br), 1.46 (9H, s), 1.07 (9H, s). 13C-NMR (125 MHz, CD3Cl,): delta 157.3, 80.2, 54.8, 28.3, 27.1.To a solution of N'-tert-Butyl-hydrazinecarboxylic acid tert-butyl ester (0.10 g, 0.5 mmol) in 3 mL THF was added Triphosgene in toluene (~1.8 M, 0.55 ml, 1.0 mmol). The reaction mixture was stirred at RT for 10 hours at RT. The solvent was removed in vacuo. The residue was dissolved in DCM (3 ml) and the solvent was removed in vacuo to provide azachloroformamide 1.-5, which was used directly in next step.
In 1,4-dioxane; sodium hydroxide;
Preparation of N'-t-butyl-N-(pyrazine-carbonyl)-N'-benzoylhydrazine To a mechanically stirred solution of t-butylhydrazine hydrochloride (51 g, 0.41 mol) in dioxane (100 ml) and water (50 ml), cooled in an ice bath was treated with 50percent sodium hydroxide (32 g). The resulting mixture was treated dropwise with di-t-butyl-dicarbonate (92 g, 0.42 mol) over about one-half of an hour. After complete addition, the reaction mixture was warmed to room temperature and stirred for 2 hours. The resulting white solid was filtered off, washed with water and air-dried to afford 74 g of N'-t-butyl-N-t-butoxycarbonylhydrazine, mp. 69-71° C.
In 1,4-dioxane; sodium hydroxide;
EXAMPLE 17 Preparation of N'-t-butyl-N-(pyrazinecarbonyl)-N'-benzoylhydrazine To a mechanically stirred solution of t-butylhydrazine hydrochloride (51 g, 0.41 mol) in dioxane (100 ml) and water (50 ml), cooled in an ice bath was treated with 50percent sodium hydroxide (32 g). The resulting mixture was treated dropwise with di-t-butyldicarbonate (92 g, 0.42 mol) over about one-half of an hour. After complete addition, the reaction mixture was warmed to room temperature and stirred for 2 hours. The resulting white solid was filtered off, washed with water and air-dried to afford 74 g of N'-t-butyl-N-t-butoxycarbonylhydrazine, m.p. 69°-71° C.
1-(5-methylchroman-6-carbonyl)-2-t-butyl hydrazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With sodium hydroxide; thionyl chloride;N,N-dimethyl-formamide; In dichloromethane; toluene;
SYNTHETIC EXAMPLE 10 Production of N-5-methylchroman-6-carbonyl-N'-t-butylhydrazine In toluene, was suspended 3.3 g of 5-methylchroman-6-carboxylic acid and to the suspension were added 2.5 ml of thionyl chloride and a catalytic amount of N,N-dimethylformamide, and the mixture was stirred at 80° C. for 2 hours. The excessive thionyl chloride and the toluene were removed by distillation, and the residue was dissolved in 10 ml of methylene chloride. To 30 ml of a methylene chloride solution containing 6.4 g of t-butylhydrazine hydrochloride, was added 34 g of a 10percent sodium hydroxide aqueous solution under cooling with ice and to the mixture was further added dropwise the previously prepared methylene chloride solution of 5-methylchroman-6-carbonyl chloride. After stirring for 30 minutes, the mixture was poured into water and extracted with methylene chloride. The methylene chloride layer was washed with saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue obtained was washed with diethyl ether to obtain 3.7 g of the titled N-5-methylchroman-6-carbonyl-N'-t-butylhydrazineN-5-methylchroman-6-carbonyl-N'-t-butylhydrazine (yield: 82percent). 1 H-NMR (CDCl3) delta(ppm): 7.12 and 6.65 (d, 2H), 5.60 (brs, 2H), 4.14 (t, 2H), 2.66 (t, 2H), 2.29 (s, 3H), 2.04 (q, 2H), 1.16 (s, 9H).
1-tert-butyl-3-methyl-5-amino-1H-pyrazole-4-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With triethylamine; In ethanol; at 85℃; for 16h;
Step 1: 5-Amino-l-toerf-butyl-3-methyl-leta-pyrazole-4-carbonitrile (Intermediate IB; R2 = t-Bu, R3 = Me); [00267] A solution of (l-ethoxyethylidene)malononitrile (25 g, 0.18 mol), tert butyl hydrazine hydrochloride (27.4 g, 0.22 mol) and triethylamine (103 mL, 0.71 mmol) in EtOH (600 mL) was heated at 85 0C for 16 h. After this time the EtOH was evaporated, and the residue partitioned between diethyl ether (500 mL) and water (300 mL). The aqueous layer was extracted with ether (500 mL) and the combined organic layers washed with brine (250 mL). The organic layer was dried over MgSpsi4 and evaporated to give a pale yellow solid (21.4 g). This solid was slurried in ether/petroleum ether, filtered and dried to give a while solid (21.2 g). The original aqueous layer and brine wash were re-extracted with ether to give additional white solid (7.2 g). The two batches of solid were combined to give the title compound as a white solid (28.4 g, 89 percent) which was used without further purification. 1H NMR (400MHz, CDCl3): 4.23 (2H, s), 2.22 (3H, s), 1.60 (9H, s).
With triethylamine; In ethanol;
EXAMPLE 35 1-tert-Butyl-3-methyl-5-amino-1H-pyrazole-4-carbonitrile To a slurry of 1-ethoxyethylidene malononitrile (68.0 g, 0.5 mol), tert-butylhydrazine hydrochloride (62.3 g, 0.5 mol) in ethanol (500 ml) was added triethylamine (70 ml, 0.5 mol). The reaction mixture was stirred at room temperature for 2 hours, cooled in an ice-bath and a solid was collected by filtration and was washed with ether. The mother liquor was concentrated and the solid residue was recrystallized from ethanol. The two solid fractions were combined and dried at 65° C. in high vacuum for 24 hours to afford 132 g of 1-tert-butyl-3-methyl-5-amino-1H-pyrazole-4-carbonitrile as a white solid which is contaminated with triethylamine hydrochloride (approximately 2/3 mol).
With triethylamine; In ethanol;
(a) To a mixture of (1-ethoxyethylidene)malononitrile (68 g, 0.5 mol) and tert-butylhydrazine hydrochloride (62.3 g, 0.5 mol) in ethanol (500 mL) was added triethylamine (70 mL, 0.5 mol). The reaction mixture was stirred at room temperature for 2 hours, then was cooled in ice and the product was collected by filtration and washed with ether to afford 85.9 g of 1-tert-butyl-3-methyl-5-amino-1H-pyrazole-4-carbonitrile 2/3 Et3 N.HCl. An additional 46.2 g of the desired product was also obtained by concentration of the mother liquor and recrystallization of the residue from ethanol.
With nitrogen; triethylamine; In dichloromethane; water;
Example 3 1-(4-Ethylbenzoyl)-2-t-butylhydrazine using alpha,alpha, alpha-trichloro-4-ethylacetophenone in methylene chloride/triethylamine To a 50 ml flask equipped with an overhead stirrer, thermometer and nitrogen is added 8.28 g (0.066 mol) of t-butylhydrazine hydrochloride. Triethylamine (6.58 g, 0.065 mol) and 15 ml of methylene chloride are added, both the triethylamine and the methylene chloride being previously dried over 3A molecular sieves. The mixture is stirred one hour, then 15.10 g (0.060 mol) of alpha,alpha, alpha-trichloro-4-ethylacetophenone are added over 45 minutes. The reaction temperature may be allowed to vary from room temperature to 40° C. during the feed. The reaction mixture is held three hours, then quenched by the addition of 15 ml of water and 5 ml of methylene chloride. The phases are separated. The organic phase is washed twice with water and 2 Normal sodium hydroxide solution, washed once with brine and stripped to yield 12.78 g off-white solids. The yield is 97percent by weight of 1-(4-ethylbenzoyl)-2-t-butylhydrazine based on the trichloroketone. The purity is analyzed as 100percent by HPLC. None of the isomer 1-(4-ethyl)benzoyl-1-t-butylhydrazine and none of the diacylated impurity 1,2-di(4-ethylbenzoyl)-1-t-butylhydrazine are detected at a limit of detection of 0.1percent.
93%
With sodium hydroxide; In dichloromethane; water;
Example 1 1-(4-Ethylbenzoyl)-2-t-butylhydrazine To a mixture of t-butylhydrazine hydrochloride (6.36 grams (g), 50 millimoles (mmol)) 5.3 g of water, 20 milliliters (ml) of methylene chloride and 4.0 g of 50percent sodium hydroxide solution (50 mmol) under nitrogen there was added dropwise at room temperature over 12 minutes alpha,alpha,alpha-trichloro-4-ethylacetophenone (13.88 g, 95.2percent purity, 52.5 mmol). The reaction mixture was stirred at room temperature for 5.75 hours, then 0.4 g of additional sodium hydroxide solution was added and the reaction mixture was stirred overnight. The reaction was quenched with water and the phases were separated. The methylene chloride phase was washed twice with water, dried over magnesium sulfate, filtered and evaporated in vacuo to yield 10.24 g (93percent yield) of a pale yellow solid.
a. 1-(3-Chlorobenzoyl)-2-t-butyl hydrazine To a suspension of t-butyl hydrazine hydrochloride (6.2 g, 0.05 mole), water (30 mL) and toluene (60 mL) at 0° C. to 5° C. was added 50percent sodium hydroxide (4.0 g, 0.05 mol). To the above reaction mixture was then added, separately and simultaneously, 50percent sodium hydroxide (4.0 g, 0.05 mol) and 3-chlorobenzoyl chloride (8.8 g, 0.05 mol) from two dropping funnels. After addition was completed, the reaction mixture was stirred at 0° C. for 30 minutes and room temperature for 30 minutes. The resultant precipitate was collected by suction-filtration and washed with water (100 mL) and dried in air to give 9.0 g (79percent yield) of 1-(3chlorobenzoyl)-2-t-butyl hydrazine as a white solid. mp 116°-118° C.
With sodium acetate; In ethanol; for 48h;Heating / reflux;
To a mixture of 5 g of 4-ethoxy-l, 1, 1-trifluoro-3-butene- 2-one, 3 g of sodium acetate and 15 ml of ethanol was added 4.6 g of tert-butylhydrazine hydrochloride, and the mixture was he.ated to reflux for 2 days. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3.0 g of l-tert-butyl-3-trifluoromethyl-lH-pyrazole of the formula: 1-tert-Butyl-3-trifluoromethyl-lH-pyrazole1H-NMR (CDCl3, TMS) delta (ppm) : 1.61 (9H, s), 6.48 (IH, d, J=2Hz) ,7.54 (IH, d, J=2Hz) .
Method 65; Ethyl 1 -fert-butyl- lH-pyrazole-3 -carboxylate; A solution of ethyl 3-formyl-4-oxobutanoate (Method 64; 350 mg, 2.2 mmol) in EtOH (5 ml) was treated with triethylamine (465 muL, 3.3 mmol) and t-butyl hydrazine hydrochloride. The reaction stirred for 12 h at 25 C. EtOH was removed under reduced pressure and the residue was redissolved in EtOAc and washed with H2O. The organics were dried with Na2SO4(S) and concentrated under reduced pressure. The residue was purified by column chromatography utilizing an Isco system (5% MeOH in CH2Cl2) to yield 327 mg (76 %) of an oil. H NMR (300 MHz): 1.29 - 1.35 (m, 3H), 1.57 (s, 9H), 4.25 (q, 2H), 7.86 (s, IH), 8.20 (s, IH).
A solution of 3-oxo-3-phenylpropanenitrile (1.5 g, 10.3 mmol) in EtOH (10 mL) was added to a slurry of tert-butylhydrazine hydrochloride (2.6 g, 20.7 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 in vacuo to give 6e as a pale yellow solid; yield: 2.2 g (97%); mp 100-102 C.
83%
To a slurry of TERT-BUTYLHYDRAZINE HYDROCHLORIDE (12.8 g, 102.9 MMOL) in 350 mL of EtOH was added sodium hydroxide (3.5 g, 88.2 MMOL). After 1 hr of stirring, a solution of 3-oxo-3-phenyl-propionitrile (10.6 g, 73.5 mmol, in 50 mL of ETOH) was added and the resulting slurry was heated to reflux. After 12 hr, the reaction was cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting solid was washed with hexanes and dried under reduced pressure to give the title compound (13.1 g, 83% yield) as yellow-colored solid, which was used without further purification. LRMS m/z (APCI) 216 (M+1); 500 MHz 1H NMR (CD30D) 8 7.67 (d, J = 7.5 Hz, 2H), 7.35-7. 29 (m, 2H), 7.25-7. 20 (m, 1H), 5.86 (s, 1 H), 1.65 (S, 9H).
45%
With triethylamine; In ethanol; for 2h;Heating / reflux;
Step 2 - Preparation of Intermediate Compound BB EPO <DP n="86"/>To a solution of benzoylacetonitrile (2.18 g, 15.0 mmol) and tert- butylhydrazine hydrochloride (2.12 g, 17.0 mmol) in ethanol (20 mL), was added triethylamine (3.5 mL, 25 mmol). The resulting reaction was heated to reflux and allowed to stir at this temperature for 2 hours. The reaction mixture was then cooled to room temperature and quenched with 5% aqueous NaOH. The resulting solution was extracted using ethyl acetate and the ethyl acetate was washed sequentially with water and brine, then dried over MgSO4 and concentrated in vacuo to provide a crude residue. The crude residue was recrystallized from CH2Cb to provide Compound B as a yellow solid (1.46 g, 45% yield). 1H NMR (400 MHz, (CD3)2SO) delta 7.64-7.58 (m, 2 H), 7.34-7.26 (m, 2 H), 7.22-7.16 (m, 1 H), 5.75 (s, 1 H), 4.94 (s, 2H), 1.55 (s, 9H).
A solution of 4-(4-chloro-phenyl)-3-oxo-butyronitrile (500 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 d, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified via automated flash chromatography (40 g SiO2, gradient from hexanes to ethyl acetate) to afford the product as a yellow oil (610 mg, 70percent).
To a slurry of tert-butylhydrazine hydrochloride (68.0 g, 546.1 mmol) in EtOH (1L) was added NaOH pellets (18.7 g, 468.1 mmol). After 30 min, crude 3-cyclobutyl-3-oxo-propionitrile in EtOH (300 mL) was added. The resulting slurry was heated to 75° C. (oil bath). After 14 hr, the reaction was cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting slurry was taken up in EtOAc and washed with saturated aqueous NaHCO3 solution. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered through a pad of diatomaceous earth, and concentrated under reduced pressure. Purification of this material was accomplished by recrystallization from 1:1 EtOAc/hexanes to yield, after several crops, the title compound (60.0 g, 80percent yield) as a colorless solid. 400 MHz 1H NMR (CDCl3) d 5.53 (s, 1H), 3.46 (bs, 2H), 3.42 (dddd, J=8.7, 8.7, 8.7, 8.7 Hz, 1H), 2.32-2.23 (m, 2H), 2.14-1.76 (m, 2H), 1.61 (s, 9H). LRMS m/z (APCI+) 194 (M+1).
80%
To a slurry of TERT-BUTYLHYDRAZINE HYDROCHLORIDE (68 g, 546 MMOL) in 1 L of EtOH was added sodium hydroxide (18. 7 g, 468.1 MMOL). After 1 hr of stirring, a solution of crude 3-cyclobutyl-3-oxo-propionitrile (390.1 MMOL, in 100 mL of ETOH) was added, and the resulting slurry was heated to reflux. After 12 hr, the reaction was cooled to room temperature, filtered, and concentrated under reduced pressure. The slurry was diluted with EtOAc and then washed with a saturated solution of NAHCO3. The organic layer was dried over MGS04, filtered through a fritted funnel, and concentrated under reduced pressure. The product was isolated by trituration with 25percent EtOAc/hexanes. After several trituration cycles, the title compound (60 g, 80percent yield) was collected as a colorless solid, which was used without further purification. LRMS m/z (APCI) 194 (M+1).
In ethanol; for 20h;Reflux;
A round bottom flask was charged with 3-cyclobutyl-3-oxo-propionitrile (CK01, 12.3 g, 0.1 mol), tert-butylhydrazine hydrochloride ([7400-27-3], 13.5 g, 0.11 mol) and EtOH (150 mL). The reaction mixture was refluxed for 20 hours and cooled down to RT. Half of the solvent was removed by concentration in vacuo, and the mixture was cooled in an ice bath. The formed precipitate was collected by filtration and washed successively with diethyl ether and n-pentane. The filtrate was allowed to stand for 1 hour, and the formed precipitate was again collected by filtration and washed with diethyl ether and w-pentane. The combined solids were stirred in ethyl acetate and a saturated solution of NaHCO3. The organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure to give the titled compound.
for 20h;Reflux;
11484] A round bottom flask was charged with 3-cyclobu- tyl-3-oxo-propionitrile (CKO1, 12.3 g, 0.1 mol), tert-butylhydrazine hydrochloride ([7400-27-3], 13.5 g, 0.11 mol) and EtOH (150 mE). The reaction mixture was refluxed for 20 hours and cooled down to RT. Half of the solvent was removed by concentration in vacuo, and the mixture was cooled in an ice bath. The formed precipitate was collected by filtration and washed successively with diethyl ether and n-pentane. The filtrate was allowed to stand for 1 hour, and the formed precipitate was again collected by filtration and washed with diethyl ether and n-pentane. The combined solids were stirred in ethyl acetate and a saturated solution of NaHCO3. The organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure to give the titled compound.
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).
To a slurry of tert-butylhydrazine hydrochloride (45.1 g, 362.0 mmol) in EtOH (1L) was added NaOH pellets (12.4 g, 310.3 mmol). After 30 min, crude 3-(3,3-dimethoxy-cyclobutyl)-3-oxo-propionitrile in EtOH (300 mL) was added. The resulting slurry was heated to 75° C. (oil bath). After 14 hr, the reaction was cooled to room temperature, filtered, and concentrated under reduced pressure. Isopropyl ether was added to the resulting slurry. The slurry was stirred for 15 min, filtered, and concentrated to yield a viscous oil. Trituration with ether/hexanes (several crops) gave the title compound (56.2 g, 86percent yield over two steps) as a colorless solid: mp 80.9° C. 500 MHz 1H NMR (CDCl3) d 5.50 (s, 1H), 3.51 (bs, 2H), 3.18 (s, 3H), 3.16 (s, 3H), 3.19-3.14 (m, 1H), 2.60-2.54 (m, 2H), 2.20-2.14 (m, 2H), 1.59 (s, 9H). LRMS m/z (APCI+) 254 (M+1).
With sodium carbonate; In acetonitrile; at 50 - 140℃;
Ih 2-tert-Butylamino-3-methyl-l-oxo-l,2-dihydro-isoquinoline-4-carboxylic acid ((S)-I- phenyl-propyl) -amide.The solution of tert-butylhydrazine for the reaction was obtained by shaking of tert- butylhydrazine hydrochloride with suspension of anhydrous Na2CO3 in acetonitrile at 50°C followed by filtration. The reaction was run at 1400C (15 min). LC-MS (m/z) 392.8 (MH+); tR = 1.55.
With sodium carbonate; In acetonitrile; at 50℃;
The solution of tert-butylhydrazine for the reaction was obtained by shaking of tert-butylhydrazine hydrochloride with suspension of anhydrous Na2CO3 in acetonitrile at 50° C. followed by filtration. The reaction was run at 140° C. (15 min). LC-MS (m/z) 392.8 (MH+); tR=1.55.
sodium methylate; In methanol; at 20℃;Inert atmosphere;
Example 1Synthesis of Dye To 28percent sodium methoxide methanol solution (60.8 g; 315 mmol) was added tert-butylhydrazine hydrochloride (B) (39.3 g; 315 mmol) at room temperature in a nitrogen stream. The mixture was stirred at room temperature for 30 minutes. The precipitate was removed by suction filtration and washed with ethanol (20 mL) to obtain a tert-butylhydrazine solution as a filtrate. Methyl 3-oxoheptanoate (A) (49.9 g; 315 mmol) was introduced into another vessel, and the tert-butylhydrazine solution was dropped thereinto while keeping the internal temperature at 40 degrees. The resultant mixture was stirred for 2 hours at an internal temperature of 60° C. and a bath temperature of 70° C. and then concentrated under vacuum. Diethyl ether (200 mL) was added thereto, and the mixture was stirred with cooling with ice. The precipitate was taken out by filtration and washed with diethyl ether to obtain first crystals (18.7 g). The mother liquor was concentrated, and the resultant precipitate was washed with hexane (200 mL) to obtain second crystals (19.8 g). The first crystals and the second crystals were brought together to obtain 38.5 g of the compound (C) (yield, 62percent). A mixture of the compound (D) (2.37 g; 12.0 mmol), water (30 mL), and concentrated hydrochloric acid (4.6 mL) was cooled with an ice bath, and a solution of sodium nitrite (870 mg; 12.6 mmol) in water (small amount) was added thereto. Thereafter, the resultant mixture was stirred for 2.5 hours with cooling with ice. Amidosulfuric acid (233 mg; 2.4 mmol) was added thereto to obtain a diazo-compound solution. Into another vessel were introduced the compound C (2.36 g; 12.0 mmol), sodium carbonate (954 mg; 9.0 mmol), and 1-N aqueous sodium hydroxide solution (10 mL). The pH of this mixture was adjusted to 11, and the mixture was cooled with ice. The diazo-compound solution was added dropwise to the mixture while maintaining a pH of 11-12 (with simultaneous dropwise addition of 2 wt percent aqueous sodium hydroxide solution). After the temperature was raised to room temperature, the precipitate was taken out by filtration and washed with water. This precipitate was purified by silica gel column chromatography (chloroform:hexane=5:1), and the solid obtained was washed with a mixed solvent composed of methanol and water. Thus, the compound (1-1) (2.16 g; yield, 44percent) was obtained.The compound (1-1) obtained was dissolved in n-decane by the following procedure and evaluated for the color of the n-decane solution, absorption maximum wavelength of the n-decane solution, gram extinction coefficient of the n-decane solution at the absorption maximum wavelength, solubility in n-decane (percent by weight), and product of the molar extinction coefficient of the n-decane solution at the absorption maximum wavelength and the molar concentration of the saturated n-decane solution. The results thereof are shown in Table 1.
Example 37 A; Synthesis of 2-(i-butyl)-4,5-dichloropyridazin-3(2H)-one (Compound 11); Solid i-butyl hydrazine hydrochloride (1 equiv) was added to a stirred solution of sodium hydroxide (0.95 equiv) dissolved in 10% water/toluene mixture (6 vol) at ambient temperature. The resulting white suspension was cooled slightly while mucochloric acid (1 equiv) was slowly added. After completion of the addition, the reaction mixture was stirred at ambient temperature for 20-30 minutes followed by dropwise addition of acetic acid (0.95 equiv). The reaction mixture was heated to 45 - 50 C and stirred for 18 h, until starting material was consumed, as measured by HPLC. The reaction solution was allowed to cool to ambient temperature and then was diluted with water (~7 vol) and the organic layer separated. The organic layer was cooled to 0 C and washed with 30% NaOH (3.6 vol), followed by 35% HC1 (3.6 vol) and water (2 x 3.6 vol). The organic solution was concentrated under vacuum and restripped with methanol (1.5 vol) to yield compound 11 as a brown solid that was dried under vacuum at 35 C (65-75% yield, 100% purity by HPLC).
With sodium acetate; In ethanol; at 80℃; for 18.0h;
tert-Butylhydrazinehydrochloride (5.99 g, 48.1 mmol) was added to EtOH (60 mL) to form a slurry. To this was added NaOAc (7.93 g, 96.7 mmol) and 2-chloroacrylonitrile (5 mL,62.6 mmol). The solution was heated to 80 C for 18 h, cooled, and the solvent removed in vacuo. The residue was slowly diluted with distilled H2O (35 mL) and partitioned between sat. aq NaHCO3 (40 mL) and EtOAc (40 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 in vacuo to afford a red oil; yield: 7.95 g (91%); bp 93-94C/0.9 Torr (yellow liquid). The product was a 5:1 mixture of the title compound 6c and its 1-tert-butyl-3-amino isomer. The crude product was used to prepare the Meldrum?s acid derivative 3c, which was purified by recrystallization (see below).
Preparation I-1A-1a: (E)-benzyl 9-(2-tert-butylhydrazono)-3-azaspiro[5.5]undec-7-ene-3-carboxylate hydrochloride salt Benzyl 9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate, Preparation I-1A-1 (4.89 g, 16.3 mmol) was dissolved in 60 ml_ ethanol and tert-butylhydrazine hydrochloride (2.44 g, 19.6 mmol) was added. The mixture was heated at reflux for 4 hours and then stirred at 60 C for 48 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to yield a tan oil which solidified on standing to yield 6.60 g (99%) of the title compound as a tan solid. 1 H NMR (400 MHz, CDCI3) ppm 7.26 - 7.42 (m, 5 H), 6.46 (d, J=10.0 Hz, 1 H), 6.26 (br. s., 1 H), 5.08 - 5.16 (m, 2 H), 3.43 - 3.58 (m, 4 H), 3.19 (s, 2 H), 1 .78 (s, 2 H), 1 .44 - 1 .63 (m, 4 H), 1 .17 - 1 .30 (m, 9 H); +ESI MS (M+H) = 370.3.
99%
In ethanol; at 60℃; for 52h;Reflux;
Step 2. (E)-benzyl 9-(2-tert-butylhydrazono)-3-azaspiro[5.5]undec-7-ene-3-carboxylate hydrochloride salt Benzyl 9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (4.89 g, 16.3 mmol) was dissolved in ethanol (60 mL) and tert-butylhydrazine hydrochloride (2.44 g, 19.6 mmol) was added. The mixture was heated at reflux for 4 hours and then stirred at 60 C. for 48 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to give a tan oil which solidified upon standing to yield 6.60 g (99%) of the title compound as a tan solid. +ESI (M+H) 370.3; 1H NMR (400 MHz, CDCl3, delta): 7.26-7.42 (m, 5H), 6.46 (d, J=10.0 Hz, 1H), 6.26 (br. s., 1H), 5.08-5.16 (m, 2H), 3.43-3.58 (m, 4H), 3.19 (s, 2H), 1.78 (s, 2H), 1.44-1.63 (m, 4H), 1.17-1.30 (m, 9H).
With triethylamine; In ethanol; for 2h;Inert atmosphere; Reflux;
Example 186-Cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid (2-tert-butyl-5-pyridin-2-yl-2H-pyrazol-3-yl)-amideStep 1: 2-tert-Butyl-5-pyridin-2-yl-2H-pyrazol-3-ylamineTo a stirred solution of 3-oxo-3-pyridin-2-yl-propionitrile (0.40 g, 2.7 mmol; CAS 54123-21-6) at r.t. in EtOH (10 ml) under an argon atmosphere were added triethylamine (1.1 ml, 8.2 mmol) and t-butylhydrazine hydrochloride (1.02 g, 8.2 mmol). The mixture was heated to reflux and stirring was continued for 2 hrs. The orange solution was cooled to r.t. The solids were filtered off. The filtrate was concentrated to leave an orange viscous oil which was taken up in EtOAc and washed with water. The aqueous layer was extracted with EtOAc and with CH2Cl2/MeOH 9:1. The combined organics were dried over MgSO4, filtered and concentrated. After silica gel chromatography using CH2Cl2/MeOH as gradient, the product was obtained as off-white solid (0.366 g, 62percent).MS: M=265.1 (M+H)+
62%
With triethylamine; In ethanol; at 20℃; for 2h;Inert atmosphere; Reflux;
Example 18: 6-Cvclopropyl-3-fpyrimidin-5-ylamino)-pyridine-2-carboxylic acid (2-tert- butyl-5-pyridin-2-yl-2H-pyrazol-3-yl)-amideStep 1: 2-tert-Butyl-5-pyridin-2-yl-2H-pyrazol-3-ylamineTo a stirred solution of 3-oxo-3-pyridin-2-yl-propionitrile (0.40 g, 2.7 mmol; CAS 54123-21-6) at r.t. in EtOH (10 ml) under an argon atmosphere were added triethylamine (1.1 ml, 8.2 mmol) and t-butylhydrazine hydrochloride (1.02 g, 8.2 mmol). The mixture was heated to reflux and stirring was continued for 2 hrs. The orange solution was cooled to r.t.. The solids were filtered off. The filtrate was concentrated to leave an orange viscous oil which was taken up in EtOAc and washed with water. The aqueous layer was extracted with EtOAc and with CE^Ck/MeOH 9: 1. The combined organics were dried over MgS04, filtered and concentrated. After silica gel chromatography using CH2Cl2/MeOH as gradient, the product was obtained as off-white solid (0.366 g, 62percent).MS: M = 265.1 (M+H)+
With triethylamine; In ethanol; at -78 - 20℃; for 3h;
Step 1: Synthesis of l-tert-butyl-4,6-dichloro-lH-pyrazolo[3,4-d]pyrimidine (0742) [00268] To a solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (5.0 g, 23.8 mmol) in EtOH (100 mL), stirred at -78°C was added Et3N (7.18 g, 71.1 mmol) followed by tert- butylhydrazine hydrochloride (2.97 g, 23.8 mmol) and the mixture was further stirred at the same temperature for lh.; the cooling bath was then removed and the mixture allowed to warm to room temperature for over 2h. The reaction mixture was concentrated and the resulting residue was purified by chromatographic column on silicagel eluted with 15percent EtOAc in petroleum ether to give l-tert-butyl-4,6-dichloro-lH-pyrazolo[3,4-d]pyrimidine (5 g, 86 percent yield) as white solid. ESI-LCMS (m/z): 245.1 found for [M+H]+.
73%
With triethylamine; In ethanol; at -78 - 0℃; for 5h;Inert atmosphere;
To 2,4,6-trichloropyrimidine-5-carbaldehyde (2 g, 9.46 mmol) in EtOH (25 mL) at -78 °C under argon were added tert-butylhydrazine hydrochloride (1.18 g, 9.46 mmol) and TEA (6 mL, 42.57 mmol) dropwise. The mixture was stirred at -78 °C for 2 h, then at 0 °C for 3 h. The mixture was then concentrated under reduced pressure onto Celite and purified by silica gel chromatography eluting with 0- 1percent) MeOH in DCM to afford l-tert-butyl-4,6-dichloro-lH-pyrazolo[3,4-d]pyrimidine (1.7 g, 73percent) as an oil that solidified upon standing. LCMS (ESI) m/z 245 (M + H)+.
Intermediate P : 1 -tert-Butyl-3-methyl-1 H-pyrazol-5-amine tert- Butylhydrazine hydrochloride (15.2 g, 122 mmol) was added to the aqueous solution of sodium hydroxide (60 mL, 2M, 122 mmol) and stirred until dissolution of a solid. To the mixture 3-aminobut-2-enenitrile (10 g, 122 mmol) was added. The reaction mixture was stirred while heating at 90°C for 18 hours, then cooled to room temperature and extracted with dichloromethane (3 chi 50 mL). Organic layers were combined, washed with brine, dried (Na2S04) and concentrated under reduced pressure to obtain title product as a white, amorphous solid with the yield of 92percent (17.2 g, 1 12 mmol). 1H NMR (500 MHz, CDCl3) delta 7.25 (t, J=8.3 Hz, 1 H), 6.50 (d, J=8.3 Hz, 2H), 3.88 (s, 6H).
ethyl 1-tert-butyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With acetic acid; In ethanol; at 60℃; for 3h;
Preparation AEthyl 1 -tert-butyl-7-oxo-4,5 ,6,7-tetrahydro- 1 H-indazole-3-carboxylate[(IV), R2 = t-butyl, A = -(CH2)2-]st. 1To a solution of ethyl (3-ethoxy-2-oxocyclohex-3-en-l-yl)(oxo)acetate 10 g (42.6 mmol) and acetic acid 5 ml in absolute ethanol (150ml) at room temperature was added tert- butyl hydrazine hydrochloride 6 g (48 mmol). The mixture was stirred at 60 °C for 3 hours. The volatiles were removed under vacuum, the residue was diluted with DCM and washed with sat. aqueous solution of NaHC03, and with brine. The organic phase was dried with sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography eluting with ethyl acetate and hexane (1 :2) to give ethyl 1-tert-butyl- 7-oxo-4,5,6,7-tetrahydro-lH-indazole-3-carboxylate in 90percent yield. LC/MS (254nm) HPLC method 2 Rt 6.08 min. 1H NMR (400 MHz, DMSO-d6) delta ppm 4.18 (q, J = 6.83 Hz, 2H) 2.93- 2.30 (3m, 6 H) 1.58 (s, 9 H), 1.16 (t, J = 6.83 Hz, 3 H). HRMS (ESI) calcd for C14H20N2O3 [M + H ]+ 287.1366 found 287.1356.According to the same method, but employing hydrazine, the following compound was prepared:Ethyl 7-oxo-4,5, 6,7-tetrahydro-lH-indazole-3-carboxylate [(IV), R2 = H, A = - (CH2)2-]. 1H NMR (400 MHz, DMSO-d6) delta ppm 14.39 (s, 1H), 4.27 (q, J= 7.11 Hz, 2H), 2.87 (t, J= 6.10 Hz, 2H), 2.51 (m, 2H), 2.04 (m, 2H), 1.28 (t, J= 7.07 Hz, 3H).
Stage #1: Piperonylic acid With 2,3,4,5,6-pentafluorophenol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 3.08h;
Stage #2: tertbutylhydrazine hydrochloride With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.0833333h;
N-tert-Butylbenzo[d][1,3]dioxole-5-carbohydrazide (19b)
EDCI (0.316 g, 1.66 mmol) at r.t., was added portionwise to a stirred slurry of benzo[d][1,3]dioxole-5-carboxylic acid (0.250 g, 1.50 mmol) and Pfp-OH (0.305 g, 1.66 mmol) dissolved in dichloromethane (2 mL) over a period of 5 minutes at r.t. The resulting slurry was stirred at r.t. for 3 hours after which a solution formed. The resulting solution was added dropwise to tert-butylhydrazine hydrochloride (0.563 g, 4.51 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.786 mL, 4.51 mmol) in dichloromethane (2 mL) at r.t. over 5 minutes. The reaction mixture was purified by preparative HPLC using a Gemini NX reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml / minute) using an isocratic mixture of 24% acetonitrile in water (containing ammonium carbonate (2 g / L). The fractions containing the desired compound were evaporated to dryness to afford N'-tert-butylbenzo[d][1,3]dioxole-5-carbohydrazide (19b, 0.194 g, 54.6 %) as a white solid: LCMS (tR = 1.92 min., purity = 100%), ESI+ m/z, 237.13 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 9.66 (d, J = 6.7 Hz, 1H), 7.44 (dd, J = 1.8, 7.8 Hz, 1H), 7.38 (d, J = 1.7 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.10 (s, 2H), 4.88 (d, J = 6.7 Hz, 1H), 1.05 (s, 9H); 13C NMR (126 MHz, DMSO-d6) δ 165.42, 150.03, 147.61, 127.32, 122.58, 108.28, 107.58, 101.99, 54.98, 27.71.
BF3.OEt2 (2.7 ml, 22.0 mmol) was added to a solution of TFEDMA (2.5 ml, 22.0 mmol) in dry dichloromethane (20 ml) under argon in a Teflon flask. The solution was stirred at room temperature for 15 min, before the dichloromethane was removed under reduced pressure. The residue was then taken up in dry acetonitrile (20 ml). In a second Teflon flask, ethyl 4,4,4-trifluoroacetoacetate (2.8 ml, 20.0 mmol) was added to a solution of pyridine (7.1 g, 90.0 mmol) in dry acetonitrile (40 ml) and the mixture was stirred at room temperature for 15 min. To this were added dropwise, at ?30° C., the contents of the first flask. The reaction mixture was brought to room temperature in the cold bath and stirred overnight. tert-Butyl hydrazine hydrochloride (3.74 g, 30.0 mmol) was added to a solution of potassium hydroxide (1.68 g, 30 mmol) in methanol (10 ml) and the mixture was stirred at room temperature for 30 minutes. This mixture was then added to the previously prepared intermediate (ethyl 2-(2,2,2-trifluoroacetyl)-3-(dimethylamino)-4,4-difluorobut-2-enoate) and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1). N-tert-Butyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acid ethyl ester (3.29 g, 10.5 mmol, 53percent) was isolated as a yellow oil. [0166] 1H NMR (CDCl3, 300 MHz, 25° C.): delta=6.80 (t, 1H, CHF2, JH-F=54.0 Hz), 4.37 (q, 2H, CH2, J=7.1 Hz), 1.70 (s, 9H, tBu), 1.36 (t, 3H, CH3, J=7.1 Hz) ppm. 13C NMR (CDCl3, 75 MHz, 25° C.): delta=161.5 (CO), 141.9 (t, CIVarom, JC-F=27.8 Hz), 131.5 (q, CIVarom, JC-F=40.6 Hz), 119.3 (q, CF3, JC-F=270.7 Hz), 116.9 (CIVarom), 109.9 (t, CHF2, JC-F=236.7 Hz), 66.0 (N?CIV tBu), 62.0 (CH2), 29.9 (q, CH3 tBu, JC-F=2.4 Hz), 13.8 (CH3) ppm. 19F NMR (CDCl3, 282 MHz, 25° C.): delta=?53.3 (CF3), ?114.4 (CHF2, JF-H=54.0 Hz) ppm.
5-[(2-tert-butylhydrazono)methyl]-4,6-dichloropyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
In N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere;
General procedure: To a 50 mL round-bottomed flask was added 1 (97percent, 500 mg, 2.74mmol), 4-methoxyphenylhydrazine hydrochloride (2a; 456 mg,2.61 mmol), and DMF (10 mL). The reaction was allowed to stir undera N2 atmosphere at r.t. for 1 h. Ice (5 g) was added with stirring,followed by a solution of NaHCO3 (330 mg, 3.9 mmol) in H2O (5mL). The resultant precipitate was filtered, washed with H2O, anddried at 40-50 °C under vacuum overnight to obtain 3a; yield: 678mg (87percent)
A mixture of <strong>[7400-27-3]tertbutylhydrazine hydrochloride</strong> (2.2 mmol; 0.282 g) and sodium carbonate (2.2 mmol; 0.233 g) inanhydrous MeOH (20 mL) is stirred at rt for 1 h. The mixture is filtered into a glass ballooncontaining 4,6,6-trimethoxy-1,1,1-trifluorohex-3-en-2-one (1) (2 mmol; 0.482 g) and stirred at65 °C for 20 h. After the reaction time, the solvent is removed under reduced pressure. The solidobtained is solubilized in chloroform and washed with distilled water (3 × 20 mL). The organiclayer is stirred with sodium carbonate and the solvent is removed again under reduced pressure.The compound is obtained as a yellow oil at 89percent yield.Yield: 89percent; 0.49 g; oil. 1H NMR (200 MHz, CDCl3): 6.5 (s, 1H, H-4), 4.6 (t, 1H, J 6.0 Hz, H-7), 3.4 (s, 6H, H-7a-b), 2.9 (d, 2H, J 6.0 Hz, H-6), 1.6 (s, 9H, But). 13C NMR (50 MHz, CDCl3): 144.8 (C-3), 131.5 (q, 2J 39 Hz, C-5), 121.5 (q, J 269 Hz, CF3), 110.1 (q, 3J 4 Hz, C-4), 103.8(C-7), 53.1 (C-7a-b), 29.9 (Me), 29,5 (C-6). GC-MS (EI, 70 eV): m/z (percent) 249 (38), 193 (83), 173(36), 149 (27), 75 (100), 57 (27). HRMS (ESI): m/z calcd for C12H19F3N2O2: 281.1477 (M + H).Found: 281.1463.
With potassium hydroxide; In water; at 20℃; for 18.25h;Inert atmosphere;
2-(2,2- Dimethylhydrazono)acetaldehyde was prepared according to a published procedure.4 A 100 mL round bottom flask was charged with a magnetic stir bar, 2-(2,2- dimethylhydrazono)acetaldehyde (1.000 g, 9.98 mmol), and water (20 mL). To this stirred solution at ambient temperature was slowly added a mixture of <strong>[7400-27-3]tert-butyl hydrazine hydrochloride</strong> (1.370 g, 1 1.00 mmol) and potassium hydroxide (0.726 g, 11.00 mmol) in water (30 mL). This solution was stirred for 15 min and was set aside for 18 hours. An oil formed initially, which converted to a yellow solid over this time. The solution was filtered and the solid was dried using a desiccator filled with P205. Light yellow crystals were obtained by sublimation at 60 °C/0.05 Torr (1.120 g, 66percent): mp 56 °C; IR (Nujol, cm"1) 3214 (m), 1559 (w), 1365 (m), 1300 (w), 1261 (w), 1229 (w) 1 132 (w), 1038 (m), 1022 (m); 'H NMR (C6D6, 23 °C, delta) 7.49 (d, 1H, (J = 8.0 Hz), CH), 7.17 (d, 1Eta, (J = 8.0 Hz), CH), 4.65 (s, broad 1Eta, NH), 2.47 (s, 6Eta, N(CH3)2), 1.14 (s, 9Eta, C(CH3)3); NMR (100 MHz, benzene-d6, 23 °C, ppm) 139.26 (s, CHN), 133.22 (s, CHN), 53.44 (s, C(CH3)3), 42.26 (s, N(CH3)2), 28.66 (s, C(CH3)3); ESI-HRMS: calcd for C8Hi9N4 ([M+H]+) 171.1610, found 171.1607.
(step 1) A solution of ethyl 3-(4-methoxyphenyl)-3-oxopropanoate (3 g, 13.5 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (2.152 mL, 16.20 mmol) in toluene (10 mL) was stirred at 90°C for 14 hr. The reaction mixture was concentrated under reduced pressure, and ethanol (15 mL) was added thereto. To the residue were added <strong>[7400-27-3]tert-butylhydrazine monohydrochloride</strong> (1.85 g, 14.85 mmol) and TEA (2.07 mL, 14.85 mmol), and the mixture was stirred at 80°C for 20 hr. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added thereto. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3?60percent ethyl acetate/hexane) to give ethyl 1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazole-4-carboxylate (2.86 g, 9.46 mmol, 70.1percent) as a pale-yellow powder. MS (API) : 303 (M+H)
(step 1) A solution of tert-butylhydrazine monohydrochloride (13.9 g, 111.55 mmol), sodium acetate (11.44 g, 139.43 mmol) and ethyl 2-(ethoxymethylene)-2-cyanoacetate (19 g, 112.31 mmol) in ethanol (130 mL) was heated under reflux for 20 hr. Ethanol was evaporated under reduced pressure, and ethyl acetate was added to the residue. The solution was washed with aqueous sodium hydrogen carbonate solution and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 2?35% ethyl acetate/hexane) to give ethyl 5-amino-1-tert-butyl-1H-pyrazole-4-carboxylate (24 g, 111.55 mmol, 102%) as a pale-yellow oil. 1H-NMR(300MHz,CDCl3):delta1.33(3H, t, J=7.16Hz), 1.63(9H, s), 4.26(2H, q, J=7.03Hz), 5.25(2H,br.s.),7.57(1H, s)
7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carloxylic acid[ No CAS ]
[ 7400-27-3 ]
N’-(tert-butyl)-7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
To a stirred solution of the boroxozole carboxylic (INX-5-49-l, 130.0 mg, 0.663 mmol) in anhydrous DMF (1 .5 ml) in a 20 ml scintillation vial purged with nitrogen were added BOP (197.0 mg, 0.663 mmol), HOBt (90.0 mg. 0.663 mmol) and DTPEA (0.579 ml, 3.32 mmol) at room temperature. The reaction mixture was stirred for 5 mm. To this was added <strong>[7400-27-3]tert-butyl hydrazine hydrochloride</strong> (105 mg, 0.84 mmol), and the reaction mixture was stirred at room temperature overnight. LCMS showed complete conversion of the boroxozole carboxylic acid a new peak. The DMF was removed using a Genevac. The sticky crude mixture was dissolved in 5percent aqueous KOH (50 ml) and EtOAc (50 ml) and extracted. The combined aqueous fractions containing the product was neutralized with 0.IN HC1 and then water was removed on a rotavapor. The residue washed with 10percent MeOFI in DCM and purified using an ISCO system. The product eluted in ?2percent MeOH in DCM give 100 mg (57percent) of the boroxazole carbohydrazide TNX-5-57-1 which was used for the next step. ?H NMR 400 MHz, DMSO-d6) oe 9.69 d, J= 6.2 Hz, 1H), 7.67 (t, J= 7.1 Hz, 1H. 7.27 (d, J22.8 Hz, 1H), 5.03 (s, 2K1, 4.92 (d, J== 7.9 Hz, IH), 1.06 (s, 9H).
N’-(tert-butyl)-1-hydioxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbohyrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
To a stirred solution of SKC-01-150 (150 mg,0.84 mmofl in anhydious DMF (1.5 ml) were added BOP (373 mg, 0.84 mmol), HOBt (129 mg, 0.84 mmol) and DIPEA (0.294 ml, 1.68 mmol) under argon at room temperature. The reaction mixture was stirred for 5 mm. To this was added <strong>[7400-27-3]tert-butyl hydrazine hydrochloride</strong> (105 mg, 0.84 mmol) and the reaction mixture was stirred at 40°C for I h. LCMS showed complete conversion of the boroxozole carboxylic acid. The reaction mixture was transferred to a scintillation vial, and tie DMF was removed using a Genevac. The sticky crude mixture was dissolved in 15percent aqueous KOH and ether. The reaction mixture was extracted with ether and washed three times with aqueous KOH. The aqueous fractions containing the product were cooled on an ice bath and 6N HC1 was added slowly to make it to pH 1-2. The mixture was extracted using ethyl acetate. The product stayed in aqueous fractions and was evaporated to dryness under vacuum. The solid KC1 was removed from the product by washing it with 5percent MeOH in DCM and collecting the filtrate to get 95percent pure product. This was further purified using an ISCO system after adsorbing the product on neutral alumina (24 g neutral alumina column, MeOH:DCM solvent mixture). The product eluted using -5percent MeOH in DCM. The fractions were collected and dried to give (0.187 g, 89percent yield) the pure boroxazole carbohydrazide SKC-02-0 11. The viscous product was dissolved in water and small amount of THF, frozen and lyophilized to get light yellow powder. ?H NMR (400 MHz, MeOD) 6 8.11 (s, 1H), 7.93 (dd, J 8.0, 1.7 Hz, 1H), 7.52 (dd, J 8.0, 0.7 Hz, 1H), 5.16 (s, 2H), 1.19 (s, 1OH).
perfluorophenyl-4-bromo-2-methyl-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate[ No CAS ]
[ 7400-27-3 ]
4-bromo-N'-(tert-butyl)-2-methyl-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With potassium carbonate; In ethanol; water; at 20℃;
EtOAc (4 ml) was added to a stirred solution of aqueous K2C03 solution (25 wtpercent, 600 mg K2C03 in 3.4 ml water) in a 200 ml round bottom flask at room temperature. To this was added tert-butyl hydrazine hydrochlorde (267 mg, 2.14 mrnol) followed by the Pf ester derivative (750 tug, 1.43 mmol) dissolved in EtOAc (3 ml). The reaction mixture was stirred at room temperature overnight. For checking the LCMS, a small amount of the sample was mixed with slightly acidic buffer solution (pH 6.5 from Aldrich) in order to quench any unreacted free hydrazine. The crude mixture was diluted with buffer solution (pH 6.5) and stirred for few minutes. LCMS showed two peaks, the major one with the expected product mass. After usual aqueous work up and extraction with ethyl acetate, the organic fractions were dried over anhydrous MgSO4, filtered and concentrated. The crude mixture was redissolved in DCM, adsorbed on silica, and purified using an ISCO system (12 g silica column, hexane/EtOAc gradient). The product eluted with -45percent EtOAc in hexane. The product fractions were collected to give 490 mg, 80percent yield of the hydrazide productSKC-02-050. ?H NMR (400 MHz, CDC13) 6 7.38 (d, J 8.2 Hz, 1H), 7.26 (s, 111), 6.96 (d, J= 8.2 Hz, 111), 4.89 (s, 1H), 4.72 (d, J= 2.8 Hz, 1H), 4.15 ? 4.03 (m, 3H), 3.97 ? 3.73 (m, 2H), 3.51-3.49 (m, 1H), 2.41 (s, 3H), 1.91 ? 1.44 (m, 6H), 1.13 (s, 9H).
5-phenyl-1-(1,1-dimethylethyl)-1H-pyrazole-3-carboxylate ethyl[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
In ethanol; at 20℃;
Example 47 Ethyl 1-(tert-butyl)-5-phenyl-1H-pyrazole-3-carboxylate To a solution of ethyl (Z)-2-hydroxy-4-oxo-4-phenylbut-2-enoate (86.3 mg, 0.392 mmol) in ethanol (2.5 mL) was slowly added tert-butyl hydrazine hydrogen chloride (50.1 mg, 0.392 mmol). The solution was stirred overnight at room temperature. When the reaction was completed as measured by TLC (Hexane:EtOAc=6:1), the reaction mixture was concentrated in vacuo. After the extraction of the concentrate with dichloromethane and water, the organic layer thus formed was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (Hexane:EtOAc=15:1?6:1) to afford the title compound (59.8 mg, 86percent, white solid). 1H NMR (300 MHz, CDCl3) delta 7.47-7.36 (m, 5H), 6.71 (s, 1H), 4.43 (q, J=7.1 Hz, 2H), 1.54 (s, 9H), 1.43 (t, J=7.1 Hz, 3H)
86%
In ethanol; at 20℃;
Without further purification, (Z)-ethyl 2-hydroxy-4-oxo-4-phenylbut-2-enoate (86.3 mg, 0.392 mmol) was slowly added to a solution of tert-butyl hydrazine hydrogen chloride (50.1 mg, 0.392 mmol) in ethanol (2.5 mL). The solution was stirred overnight at room temperature. When the reaction was completed as measured by TLC (hexane:EtOAc = 6: 1), the reaction mixture was concentrated in vacuo. After the extraction of the concentrate with dichloromethane and water, the organic layer thus formed was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (hexane:EtOAc = 15: 1 ? 6: 1) to afford the title compound (59.8 mg, 86percent). 1H NMR (300 MHz, CDCl3) delta 7.47-7.36 (m, 5H), 6.71 (s, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.54 (s, 9H), 1.43 (t, J = 7.1 Hz, 3H).
5-(4-fluorophenyl)-1-(1,1-dimethylethyl)-1H-pyrazole-3-carboxylate ethyl[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59.1 mg
With hydrogenchloride; In ethanol; water; at 20℃;
Example 55 Ethyl 1-(tert-butyl)-5-(4-fluorophenyl)-1H-pyrazole-3-carboxylate To a solution of <strong>[31686-94-9]ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate</strong> (55.9 mg, 0.235 mmol) in ethanol (2.5 mL) was slowly added tert-butyl hydrazine hydrogen chloride (48.0 mg, 0.378 mmol). Following the addition of 1M HCl 0.5 mL thereto, the reaction mixture was stirred overnight at room temperature. When the reaction was completed as monitored by TLC (Hexane:EtOAc=6:1), the reaction mixture was concentrated in vacuo. After extraction with dichloromethane and water, the organic layer thus formed was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated filtrate was purified by column chromatography (Hexane:EtOAc=6:1) to afford the title compound (59.1 mg, 87%, yellow solid). 1H NMR (300 MHz, CDCl3) delta 7.38-7.32 (m, 2H), 7.17-7.11 (m, 2H), 6.71 (s, 1H), 4.43 (q, J=7.1 Hz, 2H), 1.53 (s, 9H), 1.43 (t, J=7.1 Hz, 3H)
(E)-1-tert-butyl-2-[2-(2,4,6-trimethylphenyl)ethylidene]hydrazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With acetic acid; In methanol; at 20℃; for 24h;
Acetic acid (0.2 mL) was added to a mixture of 2-(2,4,6-trimethylphenyl)acetaldehyde (0.80 g, 4.9 mmol) and t-butylhydrazine hydrochloride (0.73 g, 4.9 mmol) in methanol (10 mL). The mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure and the residue was treated with ether (20 mL) to give a precipitate which was collected by filtration. The solid was suspended in ethyl acetate (150 mL), the pH adjusted to >7 by adding saturated NaHCO3, the organic layer washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford (E)-1-tert-butyl-2-[2-(2,4,6-trimethylphenyl)ethylidene]hydrazine (0.80 g, 70.percent) as a yellow oil. 1H NMR (300 MHz, DMSO-d6) delta 1.22 (s, 9H), 2.18 (s, 3H), 2.23 (s, 6H), 3.68 (d, J=5.2 Hz, 2H), 6.85 (s, 2H), 8.24 (t, J=5.2 Hz, 1H), 11.39 (br s, 1H). ESI-MS m/z calc. 232.2. found 233.2 (M+1)+. Retention time: 1.75 min (5 min run).
N-(2-bromo-4-(2-(tert-butyl)hydrazine-1-carbonyl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
EXAMPLE 96Synthesis of N-(2-bromo-4-(2-(tert-butyl)hydrazine- 1 -carbonyl)phenyl)acetamidecommercial SKC-1 1-055[0468] Mixed together 4-acetamido-3-bromobenzoic acid (600 mg, 2.33 mmol), PyBOP(1.21 g, 2.33 mmol) and Diisopropylethylamine (0.812 ml, 4.65 mmol) and DMF (4 ml) in a 100 ml RB flask under argon and stirred at 40 °C for 3min. To the stirred mixture, tert-butylhydrazine hydrochloride (290 mg) was added and continued to stir at 40 °C for 1.5 h. LCMS showed a single peak with the expected product mass. Removed the solvent in a genevac, diluted with EtOAc and water and extracted; the organic fractions collected and removed the solvent under vacuum. Finally purified the crude mixture using C18 column on ISCO and the major fractions (fr-29-34) collected, removed the solvent and dried to get the target compound (SKC-11-055, 587 mg, 77percent yield). LCMS: (M+l for81Br) = 330 found.
1-methyl-3-ethyl-4-chloro-1H-pyrazol-5-ylformylic acid chloride[ No CAS ]
[ 7400-27-3 ]
C11H19ClN4O[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With sodium hydroxide; In toluene; at 0 - 20℃; for 1h;
To a 250 mL reaction flask were added 100 mL of toluene, 24.8 g (0.2 mol) of t-butylhydrazine hydrochloride,Add 20g40percent NaOH solution (0.2mol), control the temperature 0 ~ 5 , dropping from the compound III and 30mL toluene mixture(0.156mol) dropwise; stirring at room temperature for 1h, distilling off toluene, filtering, washing with water,Dried and dried to obtain 326g of white solid compound IV. The total yield of the two steps was 81.0percent.
ethyl 2-(tert-butylhydrazino)-2-oxoacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With triethylamine; In dichloromethane; at 0℃; for 2h;
At 0 ,Triethylamine (3.74 g, 36.8 mmol) and tert-butylhydrazine hydrochloride (2.20 g, 17.6 mmol) were dissolved in dichloromethane (25 mL)Oxalyl chloride monoethyl ester (2.0 g, 14.7 mmol) was slowly added dropwise to the reaction system,Zero reaction for 2 hours.After the reaction,The reaction solution was diluted with methylene chloride,And then washed successively with saturated sodium bicarbonate solution,Brine.The organic phase was dried over anhydrous sodium sulfate,filter,Spin dry up2- (2- (tert-butylhydrazino) -2-oxoacetate(2g),Yield 72percent.
methyl 4-phenyl-1-(tert-butyl)isoquinoline-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With tert-Butyl peroxybenzoate; manganese(II) acetate; sodium hydrogencarbonate; In acetonitrile; at 60℃;
1 Add 21.7 g of 2-isocyano-3,3-diphenyl methacrylate to a 1000 ml reaction flask.346.8 g tert-butylhydrazine hydrochloride,289.2 grams of sodium bicarbonate,4.3 grams of manganese acetate,75.0 g tert-butyl peroxybenzoate,Acetonitrile (750 ml) was heated to 60 °C.The reaction was followed by thin layer chromatography until the reaction material disappeared;2 After the reaction is over, add water to the system to quench the reaction, extract the product with ethyl acetate, and wash the organic phase with saturated brine.After drying, remove the solvent with a rotary evaporator.Get crude product;3 The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10 : 1) to give 33.65 g of 1-tert-butyl-3-carboxylate-6-phenylisoquinoline in 80percent yield. .
YYY-4 (40 mg, 0.096 mmol) is dissolved in N,N-dimethylacetamide (1 ml). HATU (40.3 mg, 0.106 mmol) is added and the mixture is stirred to result a solution. To the resulting solution is added to <strong>[57297-29-7]cyclopropanecarboximidamide hydrochloride</strong> (17.4 mg, 144 jtmol), followed by diisopropylamine (5 1.830 iL, 0.288 mmol). The mixture is then shaken at rt for 3 hours. A solution of t-butylhydrazine hydrochloride (18 mg, 144 imol) in DMA (0.5 mL) is added followed by acetic acid (55 iL, 0.960 mmol). The mixture is shaken at 80 °C for 3 hours. The reaction mixture is purified by reverse phase HPLC to obtain Example 36.
YYY-4 (40 mg, 0.096 mmol) is dissolved in N,N-dimethylacetamide (1 ml). HATU (40.3 mg, 0.106 mmol) is added and the mixture is stirred to result in a solution. To the resulting solution is added <strong>[22007-68-7]2-methylpropanimidamide hydrochloride</strong> (17.7 mg, 144 jtmol), followed by diisopropylamine (5 1.830 iL, 0.288 mmol). The mixture is then shaken at rt for 3 hours. A solution of t-butylhydrazine hydrochloride (18 mg, 144 imol) in DMA (0.5 mL) is added followed by acetic acid (55 iL, 0.960 mmol). The mixture is shaken at 80 C for 3 hours. The reaction mixture is purified by reverse phase HPLC to obtain Example 42.
With hydrogenchloride; In ethanol; water; at 80℃; for 0.5h;Inert atmosphere;
To a solution of [1,1'-biphenyl]-4,4'-dicarboxaldehyde (200 mg, 0.95 mmol) in EtOH (10 mL), <strong>[7400-27-3]tertbutylhydrazine hydrochloride</strong> (355 mg, 2.85 mmol) and a catalytic amount of concentrated HCl (0.04 mL) were added. The reaction mixture was stirred at 80 C for30 min and the resulting solution was filtered. The residue obtained was washed with hot EtOH(25 mL) to afford compound 23b (210 mg, 63%) as a white solid: 1H NMR (500 MHz, (CD3)2SO,Fig. S53) delta 8.46 (s, 2H), 7.84 (br s, 10H), 1.31 (s, 18H); 13C NMR (100 MHz, (CD3)2SO, Fig. S54)delta 142.8, 132.1, 129.4, 128.0, 110.0, 58.6, 25.3.
3-Formyl-rifamycin SV (RAL)was purchased from LKT Laboratories Inc. (>98%). RAL (250.0mg, 0.34 mmol) was dissolved in 50 ml CH2Cl2 andrespective mixtures were prepared with each of the following compounds takenseparately: tert-butylhydrazinehydrochloride, cyclohexylhydrazine hydrochloride, 1-aminohomopiperidine,1-aminopiperidine, 1-aminopyrrolidinehydrochloride, 7-chloro-4-hydrazinoquinoline, 2-hydrazino-4,5-dihydroimidazolehydrobromide, 4-aminomorpholine, benzylhydrazine dihydrochloride, phenylhydrazinein 1 ml of CH3OH. Hydrazinescontaining hydrochloride or hydrobromide were neutralized with an equivalentamount of KOH/EtOH (0.06 mmol) solution. The mixtures were stirred at 40C forhalf an hour and after that 3/4 of the solvent volume was distilled off. Whenthe reaction was finished (control on TLC plates) the reaction mixture wasevaporated to dryness, dissolved in 50 ml of ethyl acetate and extracted three times with brine (for reactions with7-chloro-4-hydrazinoquinoline and 2-hydrazino-4,5-dihydroimidazole hydrobromide5 ml of ethanol was added). The separated organic layer was evaporated and thesynthesized derivatives of <strong>[13292-22-3]<strong>[13292-22-3]3-formylrifamycin</strong> SV</strong> (compounds 24-33) werenext purified by column chromatography with silica gel (25 cm × 1 cm, silicagel 60, 0.040-0.063 mm/230-400 mesh ASTM, Fluka) with ethyl acetate/methanol(from 1:0 to 1600:1) as an eluent. All 1H and 13C NMR data of 24-33are collected in Tables 5S - 8S.24 Yield*: 87%; HR-MALDI-TOF [M+H]+ = 796.4019; FT-IR(KBr pellet): 3463 cm-1 n(O21-H) + (O23-H), 3255 cm-1n(N-H), ), ~3000 cm-1 n(O1-H) + (O4-H) + (O8-H), ~2650 cm-1 n(N15-H · · · N38), 1716 cm-1 n(C35=O), 1651 cm-1 n(C15=O)amide + n(C11=O), 1623 cm-1 n(C=N), 1563 cm-1 d(N-H), 1522 cm-1 n(C=C), 1456 and 1418 cm-1 n(C=C), 1216 cm-1 n(C-O); Elementalanalysis C42H57N3O12: calculated:C=63.38%; H=7.22%; N=5.28%; measured: C=63.42%; H=7.19%; N=5.30%; HPLC: Rt = 5.11 min (H2O:CH3CN:buffer50:40:10);
ethyl 4-(2-tert-butylhydrazinyl)-2-(methylthio)pyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89.38%
Step-1: Synthesis of ethyl 4-(2-tert-butylhydrazinyl)-2-(methylthio)pyrimidine-5-carboxylate To a stirred solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1.66 g, 10.3 mmol, 1.2 eq) in EtOH (50 mL) was added DIPEA (4.48 g, 34.3 mmol, 4 eq) at RT. The resulting reaction mixture was stirred at RT for 30 min, followed by addition of 1 (2 g, 8.621 mmol, 1 eq) at RT. The resulting reaction mixture was stirred at RT for 3 h. The progress of reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with water (100 mL), extracted with EtOAc (2*200 mL). The combined organic layers were washed with water (100 mL), with brine (100 mL), dried over Na2SO4, concentrated under reduced pressure to afford ethyl 4-(2-tert-butylhydrazinyl)-2-(methylthio)pyrimidine-5-carboxylate (2.19 g, 89.38percent) as off white solid.
With tert.-butylnitrite; iodine; In neat (no solvent); at 25℃; for 5.5h;
General procedure: To a round-bottom flask (25 mL) was added phenylhydrazine hydrochloride 1a (43 mg, 0.3 mmol), benzonitrile 2a (0.3 mL, 3 mmol), t-BuONO (53 muL, 0.45 mmol), I2 (38 mg, 0.15 mmol), the mixture was well stirred for 6 h at 25 oC (the whole process was closely monitored by TLC). Then the reaction mixture was purified by a flash silica gel column chromatography (eluent: Petroleum ether (PE)/Ethyl acetate (EA) = 10:1) to give N-phenylbenzamide 3a as a white solid (38 mg, 64percent).
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