* 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.
Reference：
[1] Organic Mass Spectrometry, 1982, vol. 17, # 7, p. 299 - 303
[2] Journal of the American Chemical Society, 1949, vol. 71, p. 4000
2
[ 5932-27-4 ]
[ 1621-91-6 ]
Yield
Reaction Conditions
Operation in experiment
51%
Stage #1: With water; sodium hydroxide In ethanol at 20 - 80℃; Stage #2: Acidic conditions
A 2M aqueous sodium hydroxide solution (1.8 mL, 3.6 mmol) was added to a solution of ethyl 1 H-pyrazole-4-carboxylate (0.2g, 1.55 mmol) in ethanol (4 mL). The reaction mixture was stirred at room temperature overnight and at 80 °C for 2 further hours. The ethanol was evaporated and the mixture was neutralized to give a precipitate which was filtered and dried to give the title compound (0.089 g, 51percent) as a white solid.LRMS (m/z): 113 (M+1)+.
51%
With water; sodium hydroxide In ethanol at 20 - 80℃;
ethyl 1H-pyrazole-4-carboxylate (0.2g, 1.55 mmol) in ethanol (4 mL). The reaction mixture was stirred at room temperature overnight and at 80 °C for 2 further hours. The ethanol was evaporated and the mixture was neutralized to give a precipitate which was filtered and dried to give the title compound (0.089 g, 51 percent) as a white solid.LRMS (m/z): 113 (M+1)+.
To solution of ethanol (50 mL) and 3-pyrazolecarboxylicacid (1.112 g 10 mmol) at 80 °C was added concentratedsulfuric acid (2 mL), and after 2 h of stirring theethyl 1H-pyrazole-3-carboxylate was obtained (1.350 g,9.6 mmol, 96 percent).
93%
at 100℃; for 4 h; Inert atmosphere
Ethyl 1H-pyrazole-3-carboxylate (6) A 100 mL Schlenk tube was dried under vacuum, filled with nitrogen and charged with 0.5 g (4.461 mmol, 1.0 eq) 1H-pyrazol-3-carboxylic acid which was dissolved in 20 mL EtOH. After adding 1.31 g (0.72 mL, 13.382 mmol, 3.0 eq) conc. H2SO4 the colorless reaction mixture was heated to reflux (100° C.) and stirred at this temperature for 4 h. TLC analysis (DCM/MeOH 95:5) indicated full conversion of the starting material. After cooling to rt the mixture was transferred to a flask to remove the solvent at a rotary evaporator. The colorless residue was diluted in 20 mL water and neutralized with 17 mL saturated aqueous NaHCO3 solution. Thereby a white solid precipitated. The aqueous layer was extracted with EtOAc (4*50 mL), dried over MgSO4 and the solvent was evaporated under reduced pressure to yield the pure title compound. yield: 582.5 mg (93percent); colorless solid; M.p.: 158-161° C.; Rf (DCM/MeOH 95:5): 0.42; 1H-NMR (300 MHz, CDCl3): δ (ppm)=10.69 (bs, 1H, NH), 7.84 (d, 4J=2.1 Hz, 1H, Ar-H), 6.86 (d, 4J=2.1 Hz, 1H, Ar-H), 4.43 (q, 3J=7.2 Hz, 2H, CH2), 1.41 (t, 3J=7.2 Hz, 3H, CH3); 13C-NMR (75.5 MHz, CDCl3): δ (ppm)=161.8 (C=O), 141.6 (Cq), 132.3 (CHAr), 107.8 (CHAr), 61.1 (CH2), 14.3 (CH3); GC-MS (NM-50_S2): tR=4.655 min (m/z=140.1, 98.0percent M+, BP: 95.0).
92%
Reflux
1H-pyrazol-3-formic acid (7.25 g, 64.7 mmol) was dissolved in absolute ethanol (100 mL), and concentrated sulfuric acid (0.7 mL) was added. The reaction liquid was heated and refluxed overnight. The reaction liquid was concentrated in vacuo, and the residue was diluted with ethyl acetate, washed with saturated sodium bicarbonate, and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give ethyl 1H-pyrazol-3-formate (8.35g, 92percent yield), as a off-white solid. 1H NMR (400MHz, CDCl3) δ 12.4 (brs, 1H), 7.74 (d, J = 2.4 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H).
80%
Heating / reflux
1 H-Pyrazole-3-carboxylic acid (2.0 g, 17.84 mmol) was dissolved in ethanol (20 ml_), sulfonic acid (1 ml_) was added and the reaction mixture was heated to reflux overnight. Evaporation in vacuo followed by addition of water and aqueous sodium carbonate gave a white precipitate. Filtration followed by wash with water gave 1 H- pyrazole-3-carboxylic acid ethyl ester (2.0 g, 80percent) as white crystals.
72%
for 24 h; Reflux
General procedure: To a suspension of 4-methoxy-3,5-dimethylbenzoic acid (4 g, 22.2 mmol) in MeOH (60 mL) sulphuric acid was added (1 mL) and mixture stirred at reflux for 1 day. Water was added and it was extracted with AcOEt, organic layers were put together and dried over sodium sulphate and concentrated. The oil thus obtained was purified by normal phase chromatography with 5percent MeOH/DCM to yield the title compound as a colorless oil (99percent yield). LRMS: m/z 195 (M+1)+ Retention time: 6.17 min (Method B) 1H NMR (250 MHz, DMSO-d6) δ ppm 2.30 (s, 6 H) 3.74 (s, 3 H) 3.87 (s, 3 H) 7.71 (s,2H).; Obtained (72percent) from 1H-pyrazole-3-carboxylic acid following the procedure described in Preparation 117, using ethanol as solvent. LRMS: m/z 139 (M-1)+ Retention time: 2.13 min (Method A)
72%
for 12 h; Reflux
Example 14A1 lH-Pyrazole-3-carboxylic acid ethyl ester To a solution of lH-pyrazole-3-carboxylic acid (2.0 g, 17.8 mmol) in anhydrous ethanol (20 mL) was added concentrated H2SO4 (1 mL) at room temperature. The mixture was refluxed for 12 hours. TLC (neat EtOAc) indicated that the reaction was completed. The mixture was concentrated, the residue was washed with aqueous NaHC03 (20 mL), extracted with dichloromethane (50 mL x 3). The organic layer was dried over Na2S04, filtered, and concentrated in vacuum to give Example 14A1 (1.8 g, yield 72percent) as a white solid.
Reference：
[1] Journal of the Iranian Chemical Society, 2016, vol. 13, # 5, p. 823 - 830
[2] Patent: US9206115, 2015, B2, . Location in patent: Page/Page column 25-26
[3] Patent: EP3235819, 2017, A1, . Location in patent: Paragraph 0264; 0265
[4] Journal of the American Chemical Society, 2000, vol. 122, # 44, p. 10810 - 10820
[5] Patent: WO2008/92942, 2008, A2, . Location in patent: Page/Page column 20
[6] Organic Mass Spectrometry, 1982, vol. 17, # 7, p. 299 - 303
[7] Patent: EP2390252, 2011, A1, . Location in patent: Paragraph 0351; 0352; 0461; 0462
[8] Patent: WO2013/10453, 2013, A1, . Location in patent: Page/Page column 106
[9] Gazzetta Chimica Italiana, 1947, vol. 77, p. 199,205
[10] Journal of the American Chemical Society, 1949, vol. 71, p. 4000
[11] Patent: WO2008/74820, 2008, A1, . Location in patent: Page/Page column 20
[12] Patent: WO2005/111001, 2005, A1, . Location in patent: Page/Page column 104
[13] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 6, p. 1621 - 1625
7
[ 623-47-2 ]
[ 18107-18-1 ]
[ 5932-27-4 ]
Yield
Reaction Conditions
Operation in experiment
94%
at 20 - 30℃; for 4 h;
a. 1H-Pyrazole-3-carboxylic acid ethyl ester (Intermediate 74a) A solution of ethyl propiolate (10.0 g, 0.10 mol) in THF (67 mL) was treated dropwise with (trimethylsilyl)diazomethane (51 mL, 0.10 mol) maintaining the temperature between 20-30° C. with ice bath cooling. The mixture was stirred at RT for 4 h then treated cautiously with water (250 mL) with cooling in an ice bath. The organics were evaporated in vacuo and the resulting precipitate was collected by filtration, washed with water and dried at RT in vacuo to give the title compound (13.5 g, 94percent). LCMS (Method 3): Rt 2.22 min, m/z 141 [MH+].
94%
at 20 - 30℃; for 4 h;
A solution of ethyl propiolate (10.0 g, 0.10 mol) in THF (67 mL) was treated drop wise with (trimethylsilyl)diazo methane (51 mL, 0.10 mol) maintaining the temperature between 20-30 °C with ice bath cooling. The mixture was stirred at RT for 4h then treated cautiously with water (250 mL) with cooling in an ice bath. The organics were evaporated in vacuo and the resulting precipitate was collected by filtration, washed with water and dried at RT in vacuo to give the title compound (13.5 g, 94percent). LCMS (Method 3): Rt 2.22 min, m/z 141 [MH+].
90%
at 20 - 30℃; for 3 h;
Example 15, Step A[00152] To a solution of ethyl propiolate (30 g, 306 mmol) in THF (200 mL) was added dropwise trimethylsilyldiazomethane (153 mL, 2M in hexanes, 306 mmol) at 20-30°C with ice bath cooling (delayed exotherm observed). The reaction mixture was stirred for 3 hours at r.t. Water was then added (750 mL) and the organic solvents evaporated. The white precipitate was filtered and dried under vacuum to afford compound 15b (38.5 g, 90percent) as a white solid.
90%
at 20℃; for 3 h;
Example 15.[00151] Example 15 presents the preparation of Cmpd 15, N-(5-fluoropyrimidin-2-yl)- 6,7-dihydro-4H-pyrazolo[4',3':5,6]oxepino[4,3-d][1 ,3]thiazol-2-amine (Table II,Compound No. 15). Cmpd 15Example 15, Step A[00152] To a solution of ethyl propiolate (30 g, 306 mmol) in THF (200 ml.) was added dropwise trimethylsilyldiazomethane (153 ml_, 2M in hexanes, 306 mmol) at 20-30°C with ice bath cooling (delayed exotherm observed). The reaction mixture was stirred for 3 hours at r.t. Water was then added (750 mL) and the organic solvents evaporated. The white precipitate was filtered and dried under vacuum to afford compound 15b (38.5 g, 90percent) as a white solid.
Reference：
[1] Patent: US2014/364412, 2014, A1, . Location in patent: Paragraph 0729; 0730
[2] Patent: WO2014/195402, 2014, A1, . Location in patent: Page/Page column 232
[3] Green Chemistry, 2009, vol. 11, # 2, p. 156 - 159
[4] Patent: WO2012/6760, 2012, A1, . Location in patent: Page/Page column 47
[5] Patent: WO2012/8999, 2012, A2, . Location in patent: Page/Page column 47
[6] Angewandte Chemie - International Edition, 2017, vol. 56, # 22, p. 6294 - 6297[7] Angew. Chem., 2017, vol. 129, # 22, p. 6391 - 6394,4
8
[ 67751-14-8 ]
[ 5932-27-4 ]
Yield
Reaction Conditions
Operation in experiment
39%
With hydrazine dihydrochloride In ethanol at 20℃; Reflux
Step 2: lH-Pyrazole-3-carboxylic acid ethyl ester[0164] 4-Dimethylamino-2-oxo-but-3-enoic acid ethyl ester (195 g, 1.14 mol) and hydrazine dihydrochloride (119.7 g, 1 eq) were dissolved in EtOH (1 L) and stirred at room temperature overnight. The mixture was then heated to reflux for 2 hours. The reaction mixture was allowed to cool to room temperature and filtered. The solid was washed with water three times and dried. The filtrate was concentrated to a thick oil and added dropwise into a flask with stirred EtOAc (200 mL). The resulting solid was filtered and rinsed with a small amount of EtOAc. The filtered solids were combined to give the product (62 g, 39percent yield). MS (ES) mlz 141.1 (M+ H+).
8. Preparation of 3-difluorochloromethyl-NH-pyrazole from 4-butoxy-1-chloro-1,1-difluorobut-3-en-2-oneOver a period of 10 minutes, hydrazine hydrate (80percent pure, 0.52 g, 0.008 mol) was added dropwise to a solution of 4-butoxy-1-chloro-1,1-difluorobut-3-en-2-one (1.2 g, 0.005 mol) in ethanol (6 ml). The mixture was then stirred under reflux conditions for 5 h. The resulting yellow-brown suspension was concentrated on a rotary evaporator. The residue was taken up in ethyl acetate (20 ml) and water (20 ml). After separation of the phases, the aqueous phase was re-extracted with ethyl acetate (20 ml). The organic phases were combined, dried over MgSO4 and filtered, and volatile components were removed under reduced pressure. The light-red oily residue (0.35 g) consisted to about 65percent of 3-difluorochloromethyl-NH-pyrazole and to 35percent of ethyl pyrazole-3-carboxylate.3-Difluorochloromethyl-NH-pyrazole: EI-MS [m/z]: 152 [M]+; 1H-NMR (500 MHz, CDCl3): δ=6.68 (s, 1H), 7.9 (s, 1H), 11.5-13.5 ppm (s, broad, NH); 13C-NMR (125 MHz, CDCl3): δ=103.61, 124.76, 131.18, 147.91 ppm.Ethyl pyrazole-3-carboxylate: EI-MS [m/z]: 140 [M]+; 1H-NMR (500 MHz, CDCl3): δ=1.38 (t, 3H), 4.32 (q, 2H), 6.8 (s, 1H), 7.8 (s, 1H), 11.5-13.5 ppm (s, broad, NH);13C-NMR (125 MHz, CDCl3): δ=14.24, 60.2, 107.80, 132.30, 141.00, 161.60 ppm.
Reference：
[1] Journal of Chemical Research, Miniprint, 1991, # 7, p. 1701 - 1757
21
[ 623-73-4 ]
[ 74-86-2 ]
[ 5932-27-4 ]
Reference：
[1] Chemische Berichte, 1959, vol. 92, p. 970,975
22
[ 135641-75-7 ]
[ 5932-27-4 ]
[ 135641-76-8 ]
[ 135641-77-9 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1991, # 7, p. 1701 - 1757
23
[ 87879-93-4 ]
[ 140-88-5 ]
[ 87743-93-9 ]
[ 5932-27-4 ]
[ 80632-83-3 ]
Reference：
[1] Journal of Fluorine Chemistry, 1989, vol. 45, p. 323 - 330
24
[ 89600-87-3 ]
[ 7726-95-6 ]
[ 5932-27-4 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1929, vol. 470, p. 298
25
[ 5932-27-4 ]
[ 5932-34-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2018, vol. 61, # 6, p. 2384 - 2409
26
[ 80-11-5 ]
[ 623-47-2 ]
[ 5932-27-4 ]
[ 88529-79-7 ]
Reference：
[1] Journal of Organic Chemistry, 2016, vol. 81, # 14, p. 5814 - 5823
27
[ 5932-27-4 ]
[ 179692-08-1 ]
Yield
Reaction Conditions
Operation in experiment
95%
at 20℃;
Under stirring at room temperature, to a solution of ethyl 1H-pyrazol-3-formate (8.35 g, 59.6 mmol, 1.0 eq.) in acetonitrile (150 mL) was added iodine (15.6 g, 61.5 mmol, 1.03 eq.), and then ceric ammonium nitrate (32.7 g, 59.6 mmol, 1.0 eq.) was added in batches. The reaction liquid was stirred overnight at room temperature. Then, the reaction was quenched by adding 5percent NaHSO3 solution, and insoluble substances were filtered. The filter cake was washed with water and ethyl acetate. The filtrate was extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give ethyl 4-iodo-1H-pyrazol-3-formate (15.0 g, 95percent yield). 1H NMR (400MHz, CDCl3) δ 13.4 (brs, 1H), 7.89 (s, 1H), 4.46 (q, J = 7.2 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H).
89%
With N-iodo-succinimide; trifluoroacetic acid In acetonitrile at 20℃; for 3 h;
Ethylpyrazole-3-carboxylate (1.00 g, 7.14 mmol) was dissolved in acetonitrile (28 mL) N-iodosuccinimide (1.77 g, 7.85 mmol) and trifluoroacetic acid (0.16 mL, 2.14 mmol) were successively added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with a 5percent aqueous solution of sodium hydrogencarbonate and distilled water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 4: 6) to give the title compound 75-a (1.69 g, 89percent) as a yellow solid .
82%
With N-iodo-succinimide In dichloromethane at 20℃; for 24 h;
To a solution of ethyl 1H-pyrazole-3-carboxylate (10.0 g, 71.4 mmol) in DCM (30 mL) was added NIS (22.5 g, 100 mmol) at room temperature. The mixture was stirred for 24 hours. Then the reaction was quenched with H2O (50 mL) and the mixture was extracted with EtOAc (60 mL × 3) . The combined organic phase was washed with brine (50 mL × 3) and dried over Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by chromatography (PE: EtOAc 1: 5, v/v) to give the product ethyl 4-iodo-1H-pyrazole-3-carboxylate (15.5 g, 82) . m/z (ESI)+: 267 [M+H]+.
52%
With ammonium cerium (IV) nitrate; iodine In acetonitrile at 20℃; for 20 h;
Example 15, Step B[00153] To a solution of compound 15b (38.5 g, 275 mmol) in CH3CN (700 mL) was added iodine (69.8 g, 275 mmol) followed by eerie ammonium nitrate (150.7 g, 275 mmol). The reaction mixture was then stirred for 12 hours at r.t. Additional iodine (17.4 g) was added and stirring continued for 8 h, following which a cold solution of 5percent NaHS03was added to the reaction mixture. The white precipitate was filtered through a celite pad and washed with water and EtOAc. The filtrate layers were separated, the aqueous phase extracted with EtOAc and the organic phases were washed with water, dried over MgS04, filtered and solvent evaporated in vacuo to afford compound 15c (38 g, 52percent) as a slightly yellow solid.
52%
Stage #1: With ammonium cerium (IV) nitrate; iodine In acetonitrile at 20℃; for 12 h; Stage #2: With sodium hydrogen sulfite In water; ethyl acetate
Example 15, Step B[00153] To a solution of compound 15b (38.5 g, 275 mmol) in CH3CN (700 mL) was added iodine (69.8 g, 275 mmol) followed by eerie ammonium nitrate (150.7 g, 275 mmol). The reaction mixture was then stirred for 12 hours at r.t. Additional iodine (17.4 g) was added and stirring continued for 8 h, following which a cold solution of 5percent NaHSOawas added to the reaction mixture. The white precipitate was filtered through a celite pad and washed with water and EtOAc. The filtrate layers were separated, the aqueous phase extracted with EtOAc and the organic phases were washed with water, dried over MgS04, filtered and solvent evaporated in vacuo to afford compound 15c (38 g, 52percent) as a slightly yellow solid.
39%
With ammonium cerium (IV) nitrate; iodine In acetonitrile at 20℃;
b. 4-Iodo-1H-pyrazole-3-carboxylic acid ethyl ester (Intermediate 74b) A suspension of Intermediate 74a (5.00 g, 35.7 mmol) in acetonitrile (90 mL) was treated with iodine (9.10 g, 35.7 mmol) then ceric ammonium nitrate (19.6 g, 35.7 mmol) and the mixture was stirred at RT overnight. Another portion of iodine (2.28 g, 9.0 mmol) was added and the mixture was stirred for a further 24 h then treated with ice-cold aqueous sodium hydrogensulphite solution (5percent, 100 mL). The mixture was filtered through Celite rinsing with EtOAc and water. The phases were separated and the aqueous phase was extracted with EtOAc (2*). The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting solid was triturated with ether/cyclohexane, filtered off, washed with cyclohexane and dried at 50° C. in vacuo to give the title compound (3.70 g, 39percent). LCMS (Method 3): Rt 2.88 min, m/z 267 [MH+] (weak).
39%
With ammonium cerium (IV) nitrate; iodine In acetonitrile at 20℃;
A suspension of Intermediate 74a (5.00 g, 35.7 mmol) in acetonitrile (90 mL) was treated with iodine (9.10 g, 35.7 mmol) then eerie ammonium nitrate (19.6 g, 35.7 mmol) and the mixture was stirred at RT overnight. Another portion of iodine (2.28 g, 9.0 mmol) was added and the mixture was stirred for a further 24h then treated with ice-cold aqueous sodium hydrogensulphite solution (5percent, 100 mL). The mixture was filtered through Celite rinsing with EtOAc and water. The phases were separated and the aqueous phase was extracted with EtOAc (2x). The combined organic layers were washed with water and brine, dried (Na2S04), filtered and evaporated in vacuo. The resulting solid was triturated with ether/cyclohexane, filtered off, washed with cyclohexane and dried at 50°C in vacuo to give the title compound (3.70 g, 39percent). LCMS (Method 3): Rt 2.88 min, m/z 267 [MH+] (weak).
1 g
With N-iodo-succinimide In N,N-dimethyl-formamide at 20 - 60℃; for 1.5 h;
To a solution of ethyl 3-pyrazolecarboxylate (1.0 g) in N,N-dimethylformamide (7.0 mL) was added N-iodosuccinimide (1.6 g), and the mixture was stirred at room temperature for 1 hour, warmed to 60°C, and then stirred for 0.5 hours. The reaction solution was returned to room temperature, saturated aqueous sodium bicarbonate and sodium sulfite were added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and then dried over sodium sulfate. The solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain a compound 0215-1 (1.0 g) as a pale yellow solid.
To solution of ethanol (50 mL) and 3-pyrazolecarboxylicacid (1.112 g 10 mmol) at 80 °C was added concentratedsulfuric acid (2 mL), and after 2 h of stirring theethyl 1H-pyrazole-3-carboxylate was obtained (1.350 g,9.6 mmol, 96 percent).
93%
With sulfuric acid; at 100℃; for 4h;Inert atmosphere;
Ethyl 1H-pyrazole-3-carboxylate (6) A 100 mL Schlenk tube was dried under vacuum, filled with nitrogen and charged with 0.5 g (4.461 mmol, 1.0 eq) 1H-pyrazol-3-carboxylic acid which was dissolved in 20 mL EtOH. After adding 1.31 g (0.72 mL, 13.382 mmol, 3.0 eq) conc. H2SO4 the colorless reaction mixture was heated to reflux (100° C.) and stirred at this temperature for 4 h. TLC analysis (DCM/MeOH 95:5) indicated full conversion of the starting material. After cooling to rt the mixture was transferred to a flask to remove the solvent at a rotary evaporator. The colorless residue was diluted in 20 mL water and neutralized with 17 mL saturated aqueous NaHCO3 solution. Thereby a white solid precipitated. The aqueous layer was extracted with EtOAc (4*50 mL), dried over MgSO4 and the solvent was evaporated under reduced pressure to yield the pure title compound. yield: 582.5 mg (93percent); colorless solid; M.p.: 158-161° C.; Rf (DCM/MeOH 95:5): 0.42; 1H-NMR (300 MHz, CDCl3): delta (ppm)=10.69 (bs, 1H, NH), 7.84 (d, 4J=2.1 Hz, 1H, Ar-H), 6.86 (d, 4J=2.1 Hz, 1H, Ar-H), 4.43 (q, 3J=7.2 Hz, 2H, CH2), 1.41 (t, 3J=7.2 Hz, 3H, CH3); 13C-NMR (75.5 MHz, CDCl3): delta (ppm)=161.8 (C=O), 141.6 (Cq), 132.3 (CHAr), 107.8 (CHAr), 61.1 (CH2), 14.3 (CH3); GC-MS (NM-50_S2): tR=4.655 min (m/z=140.1, 98.0percent M+, BP: 95.0).
92%
With sulfuric acid;Reflux;
1H-pyrazol-3-formic acid (7.25 g, 64.7 mmol) was dissolved in absolute ethanol (100 mL), and concentrated sulfuric acid (0.7 mL) was added. The reaction liquid was heated and refluxed overnight. The reaction liquid was concentrated in vacuo, and the residue was diluted with ethyl acetate, washed with saturated sodium bicarbonate, and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give ethyl 1H-pyrazol-3-formate (8.35g, 92percent yield), as a off-white solid. 1H NMR (400MHz, CDCl3) delta 12.4 (brs, 1H), 7.74 (d, J = 2.4 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H).
80%
With sulfuric acid;Heating / reflux;
1 H-Pyrazole-3-carboxylic acid (2.0 g, 17.84 mmol) was dissolved in ethanol (20 ml_), sulfonic acid (1 ml_) was added and the reaction mixture was heated to reflux overnight. Evaporation in vacuo followed by addition of water and aqueous sodium carbonate gave a white precipitate. Filtration followed by wash with water gave 1 H- pyrazole-3-carboxylic acid ethyl ester (2.0 g, 80percent) as white crystals.
72%
With sulfuric acid; for 24h;Reflux;
General procedure: To a suspension of 4-methoxy-3,5-dimethylbenzoic acid (4 g, 22.2 mmol) in MeOH (60 mL) sulphuric acid was added (1 mL) and mixture stirred at reflux for 1 day. Water was added and it was extracted with AcOEt, organic layers were put together and dried over sodium sulphate and concentrated. The oil thus obtained was purified by normal phase chromatography with 5percent MeOH/DCM to yield the title compound as a colorless oil (99percent yield). LRMS: m/z 195 (M+1)+ Retention time: 6.17 min (Method B) 1H NMR (250 MHz, DMSO-d6) delta ppm 2.30 (s, 6 H) 3.74 (s, 3 H) 3.87 (s, 3 H) 7.71 (s,2H).; Obtained (72percent) from 1H-pyrazole-3-carboxylic acid following the procedure described in Preparation 117, using ethanol as solvent. LRMS: m/z 139 (M-1)+ Retention time: 2.13 min (Method A)
72%
With sulfuric acid; for 12h;Reflux;
Example 14A1 lH-Pyrazole-3-carboxylic acid ethyl ester To a solution of lH-pyrazole-3-carboxylic acid (2.0 g, 17.8 mmol) in anhydrous ethanol (20 mL) was added concentrated H2SO4 (1 mL) at room temperature. The mixture was refluxed for 12 hours. TLC (neat EtOAc) indicated that the reaction was completed. The mixture was concentrated, the residue was washed with aqueous NaHC03 (20 mL), extracted with dichloromethane (50 mL x 3). The organic layer was dried over Na2S04, filtered, and concentrated in vacuum to give Example 14A1 (1.8 g, yield 72percent) as a white solid.
Description 1; Ethyl 1H-pyrazole-3-carboxylate (D1); 1 H-pyrazole-3-carboxylic acid (1.Og, 8.9 mmol), was dissolved in ethanol (~12ml) and sulphuric acid added (1.5ml). the solution was heated at reflux overnight. The reaction mixture was concentrated in vacuo and water (-2OmI) added, the solution was neutralised with sodium bicarbonate. Ethylacetate (~70ml) was added and the layers partitioned, the aq was extracted with ethylacetate (~70ml) and the combined organics were dried (MgSO4) and concentrated in vacuo to yield the title compound as a white solid (1.21g, 8.64 mmol). deltaH (CDCI3, 400 MHz): 7.77 (1 H, d), 6.86 (1 H, d),4.43 (2H, quart), 1.42 (3H, t).
With sulfuric acid; for 20h;Heating / reflux;
1 - ( [2-(trimethylsilyl)ethoxy]methyl) - lH-pyrazole-3 -carbaldehyde was prepared as follows: 3-Methyl pyrazole (50 g, 0.61 mol) was placed in a 5 L round-bottom flask equipped with mechanical stirrer. 3 L of water was added and heated to 80 C. KMn04 (211.90 g, 1.34 mol) was added portion wise and refluxed for 4.5 h. After stirring at rt overnight, solid was filtered and washed with water. The water was removed in vacuo and 100 mL of water was kept in the flask which was acidified with 1 N HCl to pH 4. It was extracted with EtOAc (2x 1L), washed with brine (2x150 mL), dried over MgS04, filtered and removed in vacuo to yield 1H-pyrazole-3-carboxylic acid (38 g, 56percent) as a white solid. 38 g (0.34 mol) of IH-pyrazole-3-carboxylic acid was refluxed in anhydrous ethanol (1 L) and conc. sulfuric acid (60 mL) for 20 h under nitrogen. Ethanol was removed and crude was basified to pH 8. Precipitated solid was filtered. The filtrate was extracted with THF/CHC13 (2: 3, 3x 1 L), dried over MgS04, filtered and removed in vacuo to yield ethyl 1H-pyrazole-3- carboxylate (39 g, 82percent) as a white solid. To a suspension of ethyl 1H-pyrazole-3-carboxylate (4.42 g, 31.57 mmol) in 1,4-dioxane (140 mL) under N2 atmosphere at 0 C was added NaH (0.91 g, 37.88 mmol) and stirred for 15 min. Neat SEM-Cl (5.79 g, 34.73 mmol) was added drop wise to reaction mixture and stirred overnight at rt. It was quenched with water (30 mL) and excess 1,4-dioxane was removed in vacuo. The residue was extracted with EtOAc (2x250 mL), washed with water (1x50 mL), dried over MgS04, filtered and removed in vacuo to give crude ethyl 1 - [2- (trimethylsilyl)ethoxy]methyl}-1H pyrazole-3-carboxylate (8.84 g) as a yellow oil. The crude material was used in next step without purification. To a suspension of LiAlH4 in THF (100 mL) at 0 C under N2 atmosphere was added a solution of ethyl 1- f [2-(trimethylsilyl)ethoxy]methyl}-1H pyrazole-3-carboxylate (8.88 g, 32.88 mmol) slowly. After addition was completed the cooling bath was removed and reaction mixture was stirred overnight. It was quenched with water (10 mL) carefully at 0 C. THF was removed and residue was diluted with DCM (250 mL) and organic layer was separated, dried over MgS04 and removed in vacuo. The crude material was plugged thru a pad of silica gel with EtOAc/hexanes (from 10percent to 100percent) to yield (1-[2- (trimethylsilyl)ethoxy]methyl) -lH-pyrazol-3-yl)methanol (5.80 g, 77percent) as an yellow oil. 53.75 g (0.24 mol) of (1- f [2-(trirnethylsilyl)ethoxy]methyl}-1H pyrazol-3-yl)methanol was dissolved in THF and 122.97 g (1.41 mol) of Mn02 was added. The resulting mixture was refluxed for 60 h. Solid material was filtered through a pad of celite and washed with hot THF. The filtrate was removed in vacuo to give crude product. The crude was plugged thru a pad of silica gel and eluted with EtOAc/hexanes (from 20percent to 50percent) to yield 1-[2- (trimethylsilyl)ethoxy]methyl}-1H pyrazole-3-carbaldehyde (50.88 g, 86.5percent) as a red oil.
To a solution of ethyl-3-pyrazole carboxylate (3.53 g, 25.2 mmol) in DMF (40 mL) at 0° C. was added sodium hydride (60percent, 1.21 g, 30.2 mmol). The resulting mixture was stirred at room temperature for 40 min followed by the addition of 5-nitro-2-bromopyridine (5.1 g, 25.2 mmol). After being stirred for 20 min, the reaction mixture was partitioned between dichloromethane (1000 mL) and water (500 mL), the organic phase was washed with water (3.x.500 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography using 80percent DCM/hexane to give the desired product. To this nitro intermediate (6.77 g, 25.8 mmol) in acetic acid (220 mL) was added zinc powder (16.77 g, 258 mmol). The resulting mixture was heated at 60° C. for 30 min before it was filtered. The filtrate was concentrated in vacuum. To the residue was added DCM (1000 mL) and saturated sodium bicarbonate (1000 mL), and the resulting mixture was stirred at room temperature overnight. The organic phase was then washed with saturated sodium bicarbonate, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography using 5percent methanol in DCM (containing 0.1percent triethylamine) to give the desired product as a yellow solid. To this amine intermediate (5.96 g, 25.7 mmol) in tetrafluoroboric acid (48percent, 130 mL) at 0° C. was added a solution of sodium nitrite (1.95 g, 28.3 mmol) in water (20 mL) dropwise. The resulting solution was stirred at 0° C. for 1 h before filtration. The solid was washed with water and diethyl ether to give the desired product as a yellow solid. A mixture of this diazo intermediate (6.66 g) in acetic anhydride (250 mL) was heated at 70° C. overnight before it was concentrated in vacuo. The residue was purified by flash chromatography eluting with DCM to give the desired product as a white solid. A solution of this acetate intermediate (3.5 g, 12.7 mmol) in ethanol (400 mL) in the presence of 4 drops of sulfuric acid was heated under reflux overnight. After being concentrated in vacuo, the residue was partitioned between DCM (300 mL) and water (200 mL). The pH of the resulting mixture was adjusted to pH=5 by saturated sodium bicarbonate solution. The DCM phase was dried with sodium sulfate and concentrated in vacuo to give the product as a solid. To a solution of this hydroxyl intermediate (2.86 g, 12.3 mmol) in DMF (40 mL) at 0° C. was added sodium hydride (60percent, 589 mg, 14.73 mmol). The resulting mixture was stirred at room temperature for 40 min followed by adding 4-methoxybenzyl alcohol (2.31 g, 14.73 mmol) and sodium iodide (10 mg). The resulting mixture was heated at 80° C. for 0.5 h. After being cooled to room temperature, the reaction mixture was partitioned between DCM (500 mL) and brine (500 mL). The DCM phase was washed with brine (3.x.500 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was treated with 20percent EtOAc/hexane (50 mL) and the mixture was filtered to give the desired product. The filtrate was concentrated and the resulting residue was purified by flash chromatography using 20percent EtOAc/hexane to give additional product as a white solid. A suspension of this ethyl ester intermediate (4.13 g, 11.9 mmol) and lithium borohydride (384 mg, 17.6 mmol) in THF (300 mL) was heated under reflux overnight before it was cooled to 0° C. and quenched by 1N HCl until pH=6. The resulting mixture was diluted in EtOAc (400 mL) and washed with saturated sodium bicarbonate (2.x.400 mL), dried over sodium sulfate and concentrated in vacuo to give the desired product as a white solid. To a solution of this alcohol (3.7 g, 11.88 mmol) in DCM (200 mL) at 0° C. was added pyridine (1.13 g, 14.27 mmol), triphenylphosphine (8.73 g, 33.29 mmol) and NBS (6.34 g, 35.66 mmol). The resulting solution was stirred at 0° C. for 1.5 h. The DCM phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography eluting with DCM to give the product as a white solid. To a solution of dimethylmalonate (6.0 g, 45.6 mmol) in DMF (100 mL) at 0° C. was added sodium hydride (2.0 g, 50.15 mmol, 60percent). The mixture was stirred at 0° C. for 40 min before addition of the bromide intermediate (3.41 g, 9.12 mmol) as one portion. The resulting mixture was stirred at room temperature for 40 min before it was partitioned between ethyl acetate (500 mL) and saturated ammonium chloride (300 mL). The EtOAc phase was washed with brine (3.x.500 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography eluting with 20percent EtOAc/hexane to give the product as a white solid. To a solution of this diester (3.8 g, 8.9 mmol) in a mixture solvents of THF/MeOH/H2O (3:1:1, 300 mL) was added lithium hydroxide (1N, 150 mL) dropwise at room temperature. The solution was stirred for 40 min before it was concentrated in vacuo to remove ...
1-(5-chloro-2-[(phenylmethyl)oxy]phenylmethyl)-1H-pyrazole-3-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃;
<strong>[5932-27-4]1H-<strong>[5932-27-4]pyrazole-3-carboxylic acid ethyl ester</strong></strong> (13.0g, 93 mmol) was dissolved in dimethylformamide (200ml). Potassium carbonate (32g, 232 mmol) was added to the solution, followed by 4-chloro-2- (bromomethyl) phenyl phenylmethyl ether (29g, 93 mmol) and the reaction mixture stirred overnight at room temperature under argon. Water and ethyl acetate were added and the layers separated. The aqueous phase was re-extracted with ethyl acetate. The organic phases were combined and washed with water followed by brine. The extracts were dried (Na2SO4) and evaporated. The residue was purified by on a biotage (15-25percent ethyl acetate: hexane) to yield the title compounds. 1- ( {5-chloro-2- [ (phenylmethyl) oxy] phenyl} methyl)-<strong>[5932-27-4]1H-<strong>[5932-27-4]pyrazole-3-carboxylic acid ethyl ester</strong></strong>: (13. 90g, 40percent). t = 3.40, no ion observed.
With potassium carbonate; lithium iodide; In 1-methyl-pyrrolidin-2-one; at 80℃; for 24h;
Preparation 18 2-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-2H-pyrazole-3-carboxylic acid ETHVL ester Ethyl-pyrazole-3-carboxylate (980mg, 7. 0MMOL), 2- (2-bromoethoxy)-tetrahydro- 2H-pyran (1.57g, 7. 5MMOL), potassium carbonate (1. 01G, 7. 3MMOL) and lithium iodide (46. 8mg, 0. 35MMOL) were dissolved in 1-METHYL-2-PYRROLIDINONE (1 OML) and the reaction mixture heated to 80°C for 24 hours. The reaction mixture was allowed to cool for 17 hours and then diluted with a mixture of ethyl acetate: water 1: 1 (500mL). The organic layer was washed with water (3X250ML), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with cyclohexane : ethyl acetate 90: 10 to 80 : 20 to 75: 25 to 50: 50. The appropriate fractions were combined and concentrated in vacuo to yield the title product. HNMR (CDCI3, 400MHZ) : 1.40 (t, 3H), 1.42-1. 80 (m, 6H), 3.43 (m, 1H), 3.60 (m, 1H), 3. 78 (m, 1H), 4.04 (m, 1H), 4.35 (q, 2H), 4.55 (m, 1H), 4.82 (m, 2H), 6.81 (m, 1 H), 7. 48 (m, 1 H). MS ES+ m/z 291 [MNa] +
(b) 4-Fluoropyrazole-3-carboxylic acidSodium hydroxide (aq., 2M, 18 mmol; 9 mL) was added to a solution of a mixture (-2:1) of 4-fluoro<strong>[5932-27-4]pyrazole-3-carboxylic acid ethyl ester</strong> and <strong>[5932-27-4]pyrazole-3-carboxylic acid ethyl ester</strong> (1.2 g, ~8 mmol; see step (a) above) in dioxane (9 mL) at rt and was stirred for 16 h. A second portion of aqueous sodium hydroxide (2M, 18 mmol, 9 mL) was added and the mixture was stirred for another 4 h. The mixture was acidified with HCl (aq., 2M, 20 mL), concentrated, stirred with MeOH (30 mL) and filtered. The filtrate was concentrated and the residue crystallised from HCl (aq., 0.01M)<to give a mixture (-3:1) of the sub-title compound and pyrazole- 3-carboxylic acid as a white solid (Yield: 267 mg (-2 mmol, ~25percent)). This mixture was employed without further purification.1H-NMR (DMSO-d6): delta 13.7-13.1 (br s, 1.3H), 7.9-7.7 (m, IH), 7.73 (d, 0.3H), 6.70 (d, 0.3H).
With sodium hydroxide; water; In 1,4-dioxane; at 20℃; for 20h;
4-Fluoropyrazole-3-carboxylic acid Aqueous NaOH (2M, 18 mmol, 9 mL) was added to a solution of a mixture (~2:1) of 4-fluoro<strong>[5932-27-4]pyrazole-3-carboxylic acid ethyl ester</strong> and <strong>[5932-27-4]pyrazole-3-carboxylic acid ethyl ester</strong> (1.2 g, ~8 mmol; see step (a) above) in dioxane (9 mL) at room temperature and was stirred for 16 h. A second portion of aqueous NaOH (2M5 18 mmol, 9 mL) was added and the mixture was stirred for another 4 h. The mixture was acidified with aqueous HCl (2M, 20 mL), concentrated, stirred with MeOH (30 mL) and filtered. The filtrate was concentrated and the residue was crystallised with aqueous HCl (0.0 IM) to give a mixture (-3:1) of the sub-title compound and pyrazole-3-carboxylic acid as a white solid (Yield: 267 mg (~2 mmol, -25percent)). This mixture was employed without further purification. 1H-NMR (DMSO-d6): delta 13.7-13.1 (br s, 1.3H), 7.9-7.7 (m, IH), 7.73 (d, 0.3H), 6.70 (d, 0.3H)
With caesium carbonate;copper(I) oxide; (E)-2-hydroxylbenzaldehyde oxime; In acetonitrile; at 82℃; for 16h;
EXAMPLE 19; The fluoro bromopyridine (1 eq, Ig), pyrazole (4 eq, 5.023 g), ligand (0.2 eq, 0.196 g), Cu2O (0.05 eq, 51 mg) and Cs2CO3 (2 eq, 4.65 g) were mixed in CH3CN (8 mL) and heated to 82 0C in a sealed vessel for 16 h under N2. The solution was diluted with DCM and filtered through Celite, partitioned with water, and then brine. The product was evaporated in vacuo, and purified by column chromatography (SiO2) with 10 to 20percent EtOAc/hexanes to obtain the major regioisomeric product as a white solid. Then LiBELi (2 eq, 128 mg) was added to this ester intermediate (1 eq, 690 mg) in THF (30 mL) and heated to reflux for 15 h. Then 0.1 N HCl (a few drops) was added and stirred for 1 h, followed by a DCM/H2O partition, and the aqueous layer was basified with NaOH to pH = 9 and extracted with DCM. The combined organic phase was dried to obtain the alcohol as a white solid. Iodine (1.52 eq, l.O58g) in AcOEt (25 ml) was added to an AcOEt (25 mL ) solution of this alcohol (1 eq, 530 mg), followed by Ph3P (1.52 eq, 1.094 g) and imidazole (1.52eq, 0.284 g) over 10 min at RT. The solution was stirred for 1 h and washed with Na2S2O3 and brine. The product was dried in vacuo, and the solid residue was extracted with Hexanes 3 x 70 ml and filtered. The filtration was dried to obtain the iodide product as a white solid. Then KOtBu ( 1.5 eq, 250 mg) was added to N-(diphenylmethylene)- glycine ethyl ester (1.5 eq, 595 mg) in THF at RT and stirred for 10 min. To this solution was added the iodide intermediate (1 eq, 450 mg) in THF (5 mL) at -78 0C, and the mixture was slowly warmed to RT over 2 h. An additional 1 eq of KOtBu was added to the solution at RT and stirred for 50 h at RT. The mixture was quenched with NH4Cl and extracted with DCM, washed with H2O and then brine, and dried in vacuo. The residue was purified by column chromatography (hex/AcOEt - 20percent) to obtain the product. This intermediate (1 eq. 200 mg) was dissolved in saturated 7 N NH3/MeOH (7 mL) solution and heated to 60 0C for 24 h in a sealed tube. The reaction mixture was dried in vacuo and, the residue was dissolved in 5 ml THF and 1 N HCl (2 mL) at RT and heated to 60 0C for 20 min. The THF was removed in vacuo. The aqueous layer was washed with Et2O, dried in vacuo to obtain the amino carboxamide as a white solid HCl-salt. The amide intermediate (1 eq, 68 mg), triflate (1.2 eq, 82 mg), Pd2(DBA)3 (0.1 eq. ), Xantphos (0.2 eq, ) and Cs2CO3 (2.4 eq, 186 mg) were combined in dioxane (2 mL) under N2 and heated to 75 0C for 13 h. The mixture was cooled and diluted with CH2C12 (2 mL), filtered through Celite, and the CH2CI2 removed in vacuo, and Et2psi was added to the filtrate and extracted with 3 N HCl (3 x 10 mL). The combined aqueous layer was basified with Na2CO3 to pH== 9 at 0 0C and extracted with AcOEt (3 xlO mL). The combined organic layer was dried in vacuo to obtain the crude product as a light yellow oil. Lastly, LiOH (0.5 M, 3 mL) was added to this ester in THF/MeOH at 0 0C <n="51"/>and stirred for 20 h. Then AcOH was added to acidify to pH= 7 at 0 0C and HPLC purification provided the product. 1HNMR, CD3OD delta 8.48 (d, IH), 8.30 (d, IH), 7.99(dd, IH), 7.74 (m, IH), 6.43(d, IH), 4.37 (t, IH), 3.50(d, 2H), 2.88 (m, 2H), 2.29 (br, 2H), 1.62 (m, 4H); LCMS m/z 374 (M+H).
29 g
With copper(l) iodide; caesium carbonate; trans-N,N'-dimethylcyclohexane-1,2-diamine; In N,N-dimethyl-formamide; at 90℃; for 7h;
Reference Example 27: Ethyl-1-(5-fluoropyridin-2-yl)-1H-pyrazol-3-carboxylate To a solution of <strong>[5932-27-4]ethyl-1H-pyrazole-3-carboxylate</strong> (25.0 g, 178.4 mmol) and 2-bromo-5-fluoropyridine (47.1 g, 267.6 mmol) in DMF (300 mL), copper(I) iodide (8.5 g, 44.6 mmol), rac-trans-N,N'-dimethylcyclohexane-1,2-diamine (28.1 mL, 178.4 mmol) and Cs2CO3 (116.2 g, 356.8 mmol) were added, and the resulting mixture was stirred for 7 hours at 90°C. The reaction mixture was allowed to cool to room temperature, then water and EtOAc were added thereto, followed by filtration through Celite®. The organic layer was taken out from the filtrate, washed with a saturated aqueous solution of sodium chloride, dried over Na2SO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50 g, hexane/EtOAc = 70/30 to 0/100). The obtained solid was stirred and washed in hexane/EtOAc = 4/1 and filtered out to obtain the title compound (29.0 g) (colorless solid). MS (ESI pos.) m/z: 236 [M+H]+
With potassium tert-butylate; In N,N-dimethyl-formamide; for 0.866667h;
Description 11: 1-tert-Butoxvcarbonvlmethvl-1 H-pvrazole-4-carboxylic acid ethyl ester Potassium tert butoxide (0.045g) was added, in portions, to a stirred solution of 3- (ethoxycarbonyl) pyrazole [CAS 37622-90-5] (0.050g) in N, N- dimethylformamide (0. 5mol). The mixture was stirred for 5 min then tert- butylbromoacetate (0.078g) was added, in portions over 2 min. The mixture was stirred for 0.75h then partitioned between ethyl acetate (30moi) and 1. 0M aqueous sodium bicarbonate (20ml). The organic phase was separated, washed with water (2x20m1), dried (Na2SO4) and concentrated in vacuo to give the title compound (0.073g) as a colourless, viscous oil. LC-MS: Rt = 2.78min. Mass Spectrum m/z 255 [MH+]
With potassium tert-butylate; In ethanol; at 60℃; for 3h;
Description 36; Ethyl 1 -[(3-chloro-4-cyanophenyl)methyl]-1 H-pyrazole-3-carboxylate (D36); A suspension of ethyl 1 H-pyrazole-3-carboxylate (D1 ) (280mg, 2.0 mmol), 4- (bromomethyl)-2-chlorobenzonitrile [WO 2007/039177] (460mg, 2 mmol) and potassium t-butoxide (246mg, 2.2 mmol), in ethanol (15ml) was heated at 6O0C for 3 hours. The reaction mixture was concentrated in vacuo and dissolved in water (~25ml) and ethylacetate (~25ml), the layers were partitioned and the aq was washed twice with ethylacetate (2x 15ml). The combined organics were passed through a phase separating cartridge to dry and concentrated in vacuo. The crude product was purified by Biotage SP4 with 25S cartridge and 10-70percent ethylacetate/hexane as eluant. The product containing fractions were combined to generate two products, one of which was the title compound as a white solid (21 1 mg, 0.73 mmol). MS (ES+): requires C14H1235CIN3O2 289; found 290 (M+H+).
Description 43; Ethyl 1 -[(3-bromo-4-cyanophenyl)methyl]-1 H-pyrazole-3-carboxylate (D43); A suspension of ethyl 1 H-pyrazole-3-carboxylate (D1 ) (3.298g, 0.024 mol), 4- (bromomethyl)-2-bromobenzonitrile (D42) (6.48g, 0.024 mol) and potassium t- butoxide (2.903g, 0.026 mol), in ethanol (250ml) was heated at 6O0C overnight. The reaction mixture was concentrated in vacuo and dissolved in water (~250ml) and ethylacetate (-25OmI), the layers were partitioned and the aq was washed twice with ethylacetate (2x 100ml). The combined organics were passed through a phase separating cartridge to dry and concentrated in vacuo. The residue was scratched down and stirred in ethylacetate (~50ml) and the resultant solid was filtered off. The mother liquors were concentrated in vacuo and purified by Biotage SP4 with 4OM cartridge and 30-70percent ethylacetate/hexane as eluant. The product containing fractions were combined and concentrated. This product was combined with the first crop to yield the title compound as a white solid (1.55g, 4.6 mmol). MS (ES+): requires C14H1279BrN3O2 333; found 334 (M+H+).
With potassium tert-butylate; In ethanol; at 60℃; for 5h;
Description 6; Ethyl i-^-cyanophenylJmethyll-IH-pyrazole-S-carboxylate (D6); Benzyl bromide (12.46 g), ethyl 1 H-pyrazole-3-carboxylate (D1 ) (8.89 g) and potassium te/f-butoxide (8.75 g) were dissolved in EtOH (600 ml) and heated to 60 °C for 5 hours. The reaction mixture was then evaporated to dryness, re-dissolved in H2O and extracted with EtOAc (x 3). The combined organics were washed with brine, dried over MgSO4 and evaporated to dryness. The crude residue was purified on a large Flash 75 cartridge, eluting with a 50 percent mixture of EtOAc in hexane to give the desired isomer and then 75 percent EtOAc in hexane to give the undesired isomer. The former was recrystallized from EtOAc/hexane to give the title compound (5.24 g) as white crystals. deltaH (MeOD, 400MHz): 1.41 (3H, t), 4.42 (2H, q), 5.47 (2H, s), 6.68 (1 H, d), 7.28 (2H, d), 7.43 (1 H, d), 7.64 (2H, d). MS (ES): C14H13N3O2 requires 255.28; found 256 (M+H).
With potassium tert-butylate; In ethanol; at 60℃; for 5h;
A mixture of 3-[4-(bromomethyl)phenyl]-5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]- 1 ,2,4-oxadiazole (338mg, crude), ethyl 1 /-/-pyrazole-3-carboxylate (47mg, 0.333mmol) and potassium te/f-butoxide (41 mg, 0.366mmol) was stirred in ethanol (3.3ml) at 6O0C. The reaction was monitored by LCMS. After 5 hours the reaction mixture was evaporated to dryness, the residues were partitioned between ethyl acetate (45ml) and water (20ml). The organic phase was separated, washed with brine (20ml), dried with magnesium sulphate, filtered and evaporated to dryness. This produced 300mg of orange oil, which was purified on silica, eluting with pentane and ethyl acetate (0 to 90percent gradient). The appropriate fractions were combined and <n="24"/>evaporated to dryness. Two isomers were isolated. D3a was obtained as a white solid (30mg, 17percent over 2 steps).1H-NMR (CDCI3): delta 1.34 (3H, t), 4.31 (2H, q), 5.85 (2H, s), 6.91 (1 H, s), 7.36 (2H, d), 7.46 (5H, m), 7.58 (1 H, s), 7.89 (1 H, s), 8.08 (2H, d). MS: m/z (M+H)+ 525, C26H19F3N4O3S requires 524.63mg of yellow oil was also obtained, which was purified on a MDAP. The appropriate fractions were combined and evaporated to dryness, producing D3b as a white solid (48mg, 27percent over 2 steps).1H-NMR (CDCI3, 400MHz): delta 1.41 (3H, t), 4.43 (2H, q), 5.49 (2H, s), 6.87 (1 H, s), 7.36 (2H, d), 7.41 (1 H, s), 7.46 (5H, m), 7.90 (1 H, s), 8.13 (2H, d). MS: m/z (M+H)+ 525, C26H19F3N4O3S requires 524.
Description 14; <n="30"/>Ethyl 1 -[4-(5-{3-chloro-4-[(1 -methylethyl)oxy]phenyl}-1 ,2,4-oxadiazol-3- yl)phenyl]methyl}-1H-pyrazole-3-carboxylate (D14); [4-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1 ,2,4-oxadiazol-3-yl)phenyl]methanol (D13) (200 mg) and ethyl 1 H-pyrazole-3-carboxylate (D1 ) (85 mg) were dissolved in toluene (4.6 ml) under an Ar atmosphere and treated with tributylphosphine (152 mul). After stirring for 5 minutes 1 ,1'-azobis(N,N-dimethylformamide) (105 mg) was added and stirring continued overnight. The reaction mixture was then filtered, washing with toluene, and evaporated to dryness. The residue was purified by flash chromatography on silica, eluting with a 0-100 percent EtOAc in pentane to give the undesired isomer (86 mg) and the title compound (108 mg) in poor purity. deltaH (CDCI3, 400MHz): 1.42 (3H, t), 1.45 (6H, d), 4.43 (2H, q), 4.72 (1 H, quintet), 5.48 (2H, s), 6.87 (1 H, d), 7.06 (1 H, d), 7.36 (2H, d), 7.41 (1 H, d), 8.05 (1 H, dd), 8.14 (2H, d), 8.23 (1 H, d). MS (ES): C24H23CIN4O4 requires 466.92; found 467 (M+H).
a. 1H-Pyrazole-3-carboxylic acid ethyl ester (Intermediate 74a) A solution of ethyl propiolate (10.0 g, 0.10 mol) in THF (67 mL) was treated dropwise with (trimethylsilyl)diazomethane (51 mL, 0.10 mol) maintaining the temperature between 20-30° C. with ice bath cooling. The mixture was stirred at RT for 4 h then treated cautiously with water (250 mL) with cooling in an ice bath. The organics were evaporated in vacuo and the resulting precipitate was collected by filtration, washed with water and dried at RT in vacuo to give the title compound (13.5 g, 94percent). LCMS (Method 3): Rt 2.22 min, m/z 141 [MH+].
94%
In tetrahydrofuran; at 20 - 30℃; for 4h;
A solution of ethyl propiolate (10.0 g, 0.10 mol) in THF (67 mL) was treated drop wise with (trimethylsilyl)diazo methane (51 mL, 0.10 mol) maintaining the temperature between 20-30 °C with ice bath cooling. The mixture was stirred at RT for 4h then treated cautiously with water (250 mL) with cooling in an ice bath. The organics were evaporated in vacuo and the resulting precipitate was collected by filtration, washed with water and dried at RT in vacuo to give the title compound (13.5 g, 94percent). LCMS (Method 3): Rt 2.22 min, m/z 141 [MH+].
90%
In tetrahydrofuran; at 20 - 30℃; for 3h;
Example 15, Step A[00152] To a solution of ethyl propiolate (30 g, 306 mmol) in THF (200 mL) was added dropwise trimethylsilyldiazomethane (153 mL, 2M in hexanes, 306 mmol) at 20-30°C with ice bath cooling (delayed exotherm observed). The reaction mixture was stirred for 3 hours at r.t. Water was then added (750 mL) and the organic solvents evaporated. The white precipitate was filtered and dried under vacuum to afford compound 15b (38.5 g, 90percent) as a white solid.
90%
In hexane; at 20℃; for 3h;
Example 15.[00151] Example 15 presents the preparation of Cmpd 15, N-(5-fluoropyrimidin-2-yl)- 6,7-dihydro-4H-pyrazolo[4',3':5,6]oxepino[4,3-d][1 ,3]thiazol-2-amine (Table II,Compound No. 15). Cmpd 15Example 15, Step A[00152] To a solution of ethyl propiolate (30 g, 306 mmol) in THF (200 ml.) was added dropwise trimethylsilyldiazomethane (153 ml_, 2M in hexanes, 306 mmol) at 20-30°C with ice bath cooling (delayed exotherm observed). The reaction mixture was stirred for 3 hours at r.t. Water was then added (750 mL) and the organic solvents evaporated. The white precipitate was filtered and dried under vacuum to afford compound 15b (38.5 g, 90percent) as a white solid.
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 80℃; for 2h;
Preparation of Compound 77 Compound 75 was prepared according to J. Heterocycl. Chem., 2003, 487. Compound 75 (10 g, 71.4 mmol), compound 76 (20 g, 89.2 mmol) and K2CO3 (12.328 g, 89.2 mmol) were dissolved in NMP (60 ml), and the mixture was heated to 80° C. for 2 h. The reaction mixture was allowed to cool and diluted with a mixture of ethyl acetate: water=3:1 (500 ml). The water layer was washed with EtOAc (3.x.100 ml), and the organic layers were dried over Na2SO4, and concentrated in vacuo. The residue was purified on silica gel (PE:EA=100:1 to 20:1) to give compound 77 as yellow oil (2.2 g, 10.9percent). 1H NMR (400 MHz, CDCl3): 0.860 (q, 6H, J=4 Hz), 0.978 (m, 1H), 1.213 (m, 1H), 1.372 (t, 3H, J=7.2 Hz), 1.555 (m, 2H), 2.329 (m, 2H), 3.709 (s, 3H), 4.334 (q, 2H, J=7.2 Hz), 5.907 (q, 1H, J=5.2 Hz), 6.896 (d, 1H, J=2 Hz), 7.587 (d, 1H, J=2 Hz). MS-ESI: m/z=283.1 [M+1]+.
With N-chloro-succinimide; In N,N-dimethyl-formamide; at 20 - 45℃; for 18h;
A 5 L flange flask fitted with an overhead stirrer, condenser and temperature probe was charged with lH-<strong>[5932-27-4]pyrazole-3-carboxylic acid ethyl ester</strong> (326 g, 2.33 mol) and N,N- dimethylformamide (1.86 L). The suspension was stirred and heated to 40 0C internal temperature under nitrogen causing the precipitate to dissolve. Once dissolved, solid N- chlorosuccinimide (nuCS) (342 g, 2.56 mol) was added portionwise (10-15 g portions) over 2 h, maintaining the reaction temperature < 45 0C. When all the nuCS had been added, the reaction was allowed to cool slowly to 20 0C over 16 h. Once complete consumption of starting material had been achieved, the reaction mixture was cooled to about 15 0C and then with vigorous stirring, water (1.9 L) was added over 10 minutes. The suspension was stirred for a further 20 min and then filtered through a sinter funnel under suction. The filter cake was carefully washed twice with water (2 x 750 mL) and then with heptanes (1 x 500 mL). The filter cake was air dried and then transferred to a vacuum oven and dried overnight (60 0C, 9 mBar). The title compound was isolated as an off-white solid (330 g, 1.89 mol, 81percent) containing an impurity, 4- chloro-lH-pyrazole-3-carboxylic acid methyl ester. 1H-NMR (400 MHz, OMSO-d6): delta 14.3 (bs, IH, minor tautomer), 13.8 (bs, IH, major tautomer), 7.95 (bs, IH, major tautomer), 7.77 (bs, IH, minor tautomer), 4.40-4.20 (m, 2H, overlapping tautomers), 3.40-3.25 (bs, methyl ester impurity), 1.40-1.20 (m, 3H, overlapping tautomers).
A suspension of hydrazine hydrochloride (250 g, 3.65 mol) in methanol (1.5 L) was heated to reflux under nitrogen. At reflux, crude ethyl 4-ethoxy-2-oxo-3-butenoate (655 g, 3.65 mol) was added dropwise over 2 h. After complete addition, the reaction was allowed to cool to room temperature with stirring. After 2 h, the reaction was complete and it was cooled to 5 0C (ice bath) and the resulting precipitate was filtered and then washed with methanol (10OmL) to provide the first crop of the title compound (containing unreacted hydrazine hydrochloride, which was later removed by washing with water). The combined filtrates were concentrated under reduced pressure to give a brown syrupy residue (about 400 mL). Water (1.2 L) was added to the syrup and the mixture stirred for 30 min. The resulting solid was filtered under suction to provide a second crop of the title compound. The two product crops were combined and washed with water (2 x 100 mL) to afford the title compound as a beige solid (241 g, 47percent over two steps) containing up to 15percent w/w of lH-pyrazole-3-carboxylic acid methyl ester. 1H- NMR (400 MHz, OMSO-d6) delta 13.57 (bs, IH), 7.82 (m, IH), 6.76 (m, IH), 4.26 (q, J = 7.1 Hz, 2H), 3.80 (s, methyl ester impurity), 1.29 (t, J= 7.1 Hz, 3H).
To a suspension of sodium hydride (60percent in oil,0.45 g, 11.3 mmol, 1.6 equiv) in dry THF (16 mL) was added a solution of <strong>[5932-27-4]ethyl 1H-pyrazole-3-carboxylate</strong> (1.00 g, 7.14 mmol,1.0 equiv) in dry THF (16 mL). The resulting dark brown solution was stirred at rt for 3 h. A solution of SEM-Cl (1.52 mL, 8.56 mmol,1.2 equiv) in dry THF (6 mL) was then added dropwise at 0°C. The solution was then allowed to warm up to rt and stirred overnight. Water was added to the reaction mixture, the aqueous phase was extracted 4 times with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo togive a dark red oil. Purication by ash column chromatography (Et2O/CH2Cl2 0:100 to 5:95) led to the desired product ethyl 1-[(2-(trimethylsilyl)ethoxy)methyl]-1H-pyrazole-3-carboxylate asa light orange oil (1.22 g, 4.50 mmol, 63percent yield).
1 - ( [2-(trimethylsilyl)ethoxy]methyl) - lH-pyrazole-3 -carbaldehyde was prepared as follows: 3-Methyl pyrazole (50 g, 0.61 mol) was placed in a 5 L round-bottom flask equipped with mechanical stirrer. 3 L of water was added and heated to 80 C. KMn04 (211.90 g, 1.34 mol) was added portion wise and refluxed for 4.5 h. After stirring at rt overnight, solid was filtered and washed with water. The water was removed in vacuo and 100 mL of water was kept in the flask which was acidified with 1 N HCl to pH 4. It was extracted with EtOAc (2x 1L), washed with brine (2x150 mL), dried over MgS04, filtered and removed in vacuo to yield 1H-pyrazole-3-carboxylic acid (38 g, 56percent) as a white solid. 38 g (0.34 mol) of IH-pyrazole-3-carboxylic acid was refluxed in anhydrous ethanol (1 L) and conc. sulfuric acid (60 mL) for 20 h under nitrogen. Ethanol was removed and crude was basified to pH 8. Precipitated solid was filtered. The filtrate was extracted with THF/CHC13 (2: 3, 3x 1 L), dried over MgS04, filtered and removed in vacuo to yield ethyl 1H-pyrazole-3- carboxylate (39 g, 82percent) as a white solid. To a suspension of <strong>[5932-27-4]ethyl 1H-pyrazole-3-carboxylate</strong> (4.42 g, 31.57 mmol) in 1,4-dioxane (140 mL) under N2 atmosphere at 0 C was added NaH (0.91 g, 37.88 mmol) and stirred for 15 min. Neat SEM-Cl (5.79 g, 34.73 mmol) was added drop wise to reaction mixture and stirred overnight at rt. It was quenched with water (30 mL) and excess 1,4-dioxane was removed in vacuo. The residue was extracted with EtOAc (2x250 mL), washed with water (1x50 mL), dried over MgS04, filtered and removed in vacuo to give crude ethyl 1 - [2- (trimethylsilyl)ethoxy]methyl}-1H pyrazole-3-carboxylate (8.84 g) as a yellow oil. The crude material was used in next step without purification. To a suspension of LiAlH4 in THF (100 mL) at 0 C under N2 atmosphere was added a solution of ethyl 1- f [2-(trimethylsilyl)ethoxy]methyl}-1H pyrazole-3-carboxylate (8.88 g, 32.88 mmol) slowly. After addition was completed the cooling bath was removed and reaction mixture was stirred overnight. It was quenched with water (10 mL) carefully at 0 C. THF was removed and residue was diluted with DCM (250 mL) and organic layer was separated, dried over MgS04 and removed in vacuo. The crude material was plugged thru a pad of silica gel with EtOAc/hexanes (from 10percent to 100percent) to yield (1-[2- (trimethylsilyl)ethoxy]methyl) -lH-pyrazol-3-yl)methanol (5.80 g, 77percent) as an yellow oil. 53.75 g (0.24 mol) of (1- f [2-(trirnethylsilyl)ethoxy]methyl}-1H pyrazol-3-yl)methanol was dissolved in THF and 122.97 g (1.41 mol) of Mn02 was added. The resulting mixture was refluxed for 60 h. Solid material was filtered through a pad of celite and washed with hot THF. The filtrate was removed in vacuo to give crude product. The crude was plugged thru a pad of silica gel and eluted with EtOAc/hexanes (from 20percent to 50percent) to yield 1-[2- (trimethylsilyl)ethoxy]methyl}-1H pyrazole-3-carbaldehyde (50.88 g, 86.5percent) as a red oil.
Intermediates 72 and 73Ethyl 1-(2-fluoroethyl)-1H-pyrazole-5-carboxylate and ethyl 1-(2-fluoroethyl)-1H- pyrazole-3-carboxylate To a solution of ethyl 1 H-pyrazole-3-carboxylate (0.77g) (available from ABCR) in acetonitrile (30ml) was added cesium carbonate (1.79g) and the mixture stirred for 5min when 1-fluoro-2-iodoethane (0.96g) was added and the mixture stirred at 200C for 18h.The mixture was evaporated and the residue taken up in water (30ml) and DCM (30ml) separated by hydrophobic frit and concentrated to ~5ml, placed on an SPE cartridge (5Og silica) and eluted with a gradient of ethyl acetate in cyclohexane to give the Ethyl 1-(2- fluoroethyl)-1 H-pyrazole-5-carboxylate (0.42g) as a colourless oil.LC/MS R1 2.09 min m/z 186 [MH+]. Method C and ethyl 1-(2-fluoroethyl)-1 H-pyrazole-3-carboxylate (g) as a colourless oilLC/MS R1 1.73 min m/z 186 [MH+]. Method C
With sodium ethanolate; In tetrahydrofuran; ethanol; for 16h;Reflux;
Step 3: l-Isopropyl-lH-pyrazole-S-carboxylic acid ethyl ester[0165] To lH-<strong>[5932-27-4]pyrazole-3-carboxylic acid ethyl ester</strong> (23.1g, 165 mmol) in THF (330 mL) was added 2-iodopropane (33.OmL, 330 mmol) followed by NaOEt (21percent in EtOH, 65.0 mL, 174 mmol). This solution was then heated to reflux for 16 h. The reaction was then allowed to cool to room temperature. AcOH (10.5 mL, 183 mmol) was added and the reaction was stirred for 5 min. H2O (400 mL) was added to the solution, and this mixture was extracted with EtOAc (3x150 mL). The combined organic was washed with sat. aq. NaHCO3, then brine. The organic was dried over MgSO4, filtered, and concentrated to give the product (28.7Og, 96percent) as a brown oil containing a 98:2 mixture of regioisomers by 1H NMR.
With hydrazine dihydrochloride; In ethanol; at 20℃;Reflux;
Step 2: lH-Pyrazole-3-carboxylic acid ethyl ester[0164] 4-Dimethylamino-2-oxo-but-3-enoic acid ethyl ester (195 g, 1.14 mol) and hydrazine dihydrochloride (119.7 g, 1 eq) were dissolved in EtOH (1 L) and stirred at room temperature overnight. The mixture was then heated to reflux for 2 hours. The reaction mixture was allowed to cool to room temperature and filtered. The solid was washed with water three times and dried. The filtrate was concentrated to a thick oil and added dropwise into a flask with stirred EtOAc (200 mL). The resulting solid was filtered and rinsed with a small amount of EtOAc. The filtered solids were combined to give the product (62 g, 39percent yield). MS (ES) mlz 141.1 (M+ H+).
8. Preparation of 3-difluorochloromethyl-NH-pyrazole from 4-butoxy-1-chloro-1,1-difluorobut-3-en-2-oneOver a period of 10 minutes, hydrazine hydrate (80percent pure, 0.52 g, 0.008 mol) was added dropwise to a solution of 4-butoxy-1-chloro-1,1-difluorobut-3-en-2-one (1.2 g, 0.005 mol) in ethanol (6 ml). The mixture was then stirred under reflux conditions for 5 h. The resulting yellow-brown suspension was concentrated on a rotary evaporator. The residue was taken up in ethyl acetate (20 ml) and water (20 ml). After separation of the phases, the aqueous phase was re-extracted with ethyl acetate (20 ml). The organic phases were combined, dried over MgSO4 and filtered, and volatile components were removed under reduced pressure. The light-red oily residue (0.35 g) consisted to about 65percent of 3-difluorochloromethyl-NH-pyrazole and to 35percent of ethyl pyrazole-3-carboxylate.3-Difluorochloromethyl-NH-pyrazole: EI-MS [m/z]: 152 [M]+; 1H-NMR (500 MHz, CDCl3): delta=6.68 (s, 1H), 7.9 (s, 1H), 11.5-13.5 ppm (s, broad, NH); 13C-NMR (125 MHz, CDCl3): delta=103.61, 124.76, 131.18, 147.91 ppm.Ethyl pyrazole-3-carboxylate: EI-MS [m/z]: 140 [M]+; 1H-NMR (500 MHz, CDCl3): delta=1.38 (t, 3H), 4.32 (q, 2H), 6.8 (s, 1H), 7.8 (s, 1H), 11.5-13.5 ppm (s, broad, NH);13C-NMR (125 MHz, CDCl3): delta=14.24, 60.2, 107.80, 132.30, 141.00, 161.60 ppm.
Intermediate 14: Ethyl 1 -U2-(phenyloxy)phenvpimethyl)-1H-pyrazole-3- carboxylate; To ethyl 1 H-pyrazole-3-carboxylate (1.05 g, 75 mmol, ChemCollect GmbH) in DMF (10 ml) under nitrogen was added sodium hydride (315 mg, 7.88 mmol) and the mixture stirred at room temperature for 10 min. To this mixture was added 1- (bromomethyl)-2-(phenyloxy)benzene (1.97 g, 7.5 mmol, Maybridge) and the mixture left to stir at room temperature for 1 h. The reaction quenched with water and extracted with ethyl acetate (3 x). The combined extracts were washed with -10percent lithium chloride solution in water (3 x), the organic layer dried over magnesium sulphate, the drying agent filtered off and the filtrate evaporated to dryness to leave an oil (2.55 g). This was applied to silica SPE (10Og) cartridge, eluting with DCIWEtOAc 0-50percent over 60 min. The pure fractions were combined and evaporated to dryness to leave the title compound as dark oil (2.1 g); LCMS: (System 4) MH+= 323, tRET = 3.08 min.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 24h;Inert atmosphere;
Intermediate 16: Ethyl 1 -U2-(putyloxy)phenyl1methyl'HH-pyrazole-3- carboxylate; To ethyl 1 H-pyrazole-3-carboxylate (1.74 g, 12.4 mmol, ChemCollect GmbH) and potassium carbonate (3.43 g, 24.8 mmol) was added 1-(bromomethyl)-2- (butyloxy)benzene (3.0 g, 12.3 mmol) as a solution in DMF, washing in with further DMF to give a total volume of 35 ml. The mixture was stirred under nitrogen at ambient temperature. After 24 h the reaction was concentrated in vacuo. The residue was partitioned between EtOAc and water (approximately 100 ml each). The layers were separated and the aqueous was extracted with further EtOAc (2 x 50 ml). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give a pale yellow oil, which partially solidified on standing. The material was loaded in dichloromethane and purified on silica (Si) 100 g using 0- 100percent ethyl acetate-cyclohexane. The appropriate fractions were combined and concentrated in vacuo to give the title compound (2.07 g); LCMS: (System 4) MH+ = 303, tRET = 3.27 min.
To a suspension of <strong>[5932-27-4]1H-<strong>[5932-27-4]pyrazole-3-carboxylic acid ethyl ester</strong></strong> (12.0 g, 85.67 mmol) in THF (250 mL) at 0 C. was added NaH (3.08 g, 128.51 mmol) in small portions. The mixture was stirred for 30 min. Then 2-fluoro-1-bromo ethane (11.87 g, 94.24 mmol) was added. The temperature was slowly increased to 80 C. and the mixture was left with stirring overnight. The mixture was quenched with ice-cold water and extracted with EtOAc (2*150 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness. Flash chromatography (silica, EtOAc:petroleum ether 3:7) gave 1-(2-fluoro-ethyl)-<strong>[5932-27-4]1H-<strong>[5932-27-4]pyrazole-3-carboxylic acid ethyl ester</strong></strong> as an off-white solid (7.5 g, 47%).
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 100℃; for 48h;Sealed tube;
Step 1:; To a solution of 1 H-<strong>[5932-27-4]pyrazole-3-carboxylic acid ethyl ester</strong> S (500 mg, 3.57 mmol) in DMF (6.5 mL) is added K2C03 (542 mg, 3.93 mmol, 1.10 equiv), Nal (1.07 g, 7.14 mmol, 2 equiv) and 1-bromo-2-fluoroethane (928 mg, 7.14 mmol, 2.00 equiv). The reaction mixture is stirred at 100 C for 48 h in a closed vial. The reaction is quenched with HCI 1 N (pH ~5-6), water is added and the mixture is extracted with EtOAc (5x). The organics are washed with brine, dried with anhydrous MgS04, filtered and concentrated. The crude mixture containing the 2 regioisomers is purified by prep HPLC. The appropriate fractions are combined, frozen and lyophilized to give Td.UPLC-MS: 186.8 (M+H)+ 1H NMR (400 MHz, DMSO-d6) delta (ppm): 7.90 (d, J = 2.4 Hz, 1 H), 6.76 (d, J = 2.4 Hz, 1 H), 4.79 (dt, J = 47.3, 4.7 Hz, 2H), 4.53 (dt, J = 27.8, 4.7 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H).
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 100℃; for 48h;
Step 1:; To a solution of 1 H-<strong>[5932-27-4]pyrazole-3-carboxylic acid ethyl ester</strong> 9a (500 mg, 3.57 mmol) in DMF (6.5 mL) is added K2C03 (542 mg, 3.93 mmol, 1 .10 equiv), Nal (1 .07 g, 7.14 mmol, 2.00 equiv) and 1 -bromo-2-fluoroethane (928 mg, 7.14 mmol, 2.00 equiv). The reaction mixture is stirred at 100 C for 48 h in a closed vial. The reaction is quenched with HCI 1 N (pH ~5-6), water is added and the mixture is extracted with EtOAc (5x). The organics are washed with brine, dried with anhydrous MgS04, filtered and concentrated. The crude mixture containing the 2 regioisomers is purified by prep HPLC. The appropriate fractions are combined, frozen and lyophilized to give 9g.UPLC-MS: 186.8 (M+H)+ 1H NMR (400 MHz, DMSO-d6) delta (ppm): 7.90 (d, 1 H, J = 2.4 Hz), 6.76 (d, 1 H, J = 2.4 Hz), 4.79 (dt, 2H, J = 47.3, 4.7 Hz), 4.53 (dt, 2H, J = 27.8, 4.7 Hz), 4.26 (q, 2H, J = 7.1 Hz), 1 .28 (t, 3H, J = 7.1 Hz).
With caesium carbonate; In acetonitrile; at 20℃; for 18.5h;
To a solution of ethyl 1 H-pyrazole-3-carboxylate (2 g) in MeCN (40 ml) was added cesium carbonate (4.65 g) and the mixture stirred for 30 min when 4-(bromomethyl)tetrahydro-2H- pyran (2.81 g) was added and the mixture stirred at RT for 18 h. The solvent was removed in vacuo and the residue partitioned between dichloromethane (50 ml) and water (20 ml), separated by hydrophobic frit and concentrated. The filtrate was purified by silica (2 x 100 g) cartridge on Flashmaster II using a gradient of DCM and ethyl acetate to give the title compound 1 as a colourless oil, 0.944 g and title compound 2, as a colourless oil, 1 .026g.1 ; LCMS (method B); Rt = 0.90 min, MH+ = 239.2; LCMS (method B); Rt = 0.75 min, MH+ = 239.
A 2M aqueous sodium hydroxide solution (1.8 mL, 3.6 mmol) was added to a solution of ethyl 1 H-pyrazole-4-carboxylate (0.2g, 1.55 mmol) in ethanol (4 mL). The reaction mixture was stirred at room temperature overnight and at 80 °C for 2 further hours. The ethanol was evaporated and the mixture was neutralized to give a precipitate which was filtered and dried to give the title compound (0.089 g, 51percent) as a white solid.LRMS (m/z): 113 (M+1)+.
51%
With water; sodium hydroxide; In ethanol; at 20 - 80℃;
<strong>[5932-27-4]ethyl 1H-pyrazole-4-carboxylate</strong> (0.2g, 1.55 mmol) in ethanol (4 mL). The reaction mixture was stirred at room temperature overnight and at 80 °C for 2 further hours. The ethanol was evaporated and the mixture was neutralized to give a precipitate which was filtered and dried to give the title compound (0.089 g, 51 percent) as a white solid.LRMS (m/z): 113 (M+1)+.
With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃; for 4h;Schlenk technique; Inert atmosphere;
In a round bottom Schlenk flask under argon 2,6-difluoro-4-bromopyridyne (1 g, 5.15 mmol) and 3-ethoxycarbonyl pyrazole (1.44 g, 10.3 mmol) were dissolved in 30 mL of dry THF. The solution was cooled to 0 °C and NaH (60percent in oil, 452 mg, 11.3 mmol) was added. The reaction mixture was left at rt. for 4 h, after which 20 mL of CH2Cl2 was added. The organic phase was washed with water (20 mL) and the aqueous phase was extracted with CH2Cl2 (3 * 10 mL). The combined organic phases were dried over Na2SO4 and concentrated to dryness to afford a solid that was purified by flash chromatography (CH2Cl2/hexane 1:1) to a white solid 2 g, 89percent. 1H NMR (CDCl3, 300 MHz) delta: 8.55 (2H, d, J = 2.6 Hz), 8.28 (2H, s), 7.01 (2H, d, J = 2.6 Hz), 4.46 (4H, q, J = 7.1 Hz), 1.44 (6H, t, J = 7.2 Hz).ppm; 13C NMR (CDCl3, 75 MHz) delta: 161.7; 149.7; 146.9; 137.4; 128.6; 114.6; 110.7; 61.5; 14.3 ppm. Anal. Calc. for C17H16BrN5O4: C 47.02, H 3.71, N 16.13, found: C 46.82, H 3.57, N 15.92; MS (EI + ): m/z = 433.0 ([M + H]+, 100percent), 435.0 ([M + H]+ + 2, 97percent)
2-[(4R,6S)-8-chloro-6-(2,3-dimethoxyphenyl)-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl]ethyl methanesulfonate[ No CAS ]
[ 5932-27-4 ]
[ 937055-78-2 ]
[ 937055-29-3 ]
Yield
Reaction Conditions
Operation in experiment
9%; 10%
To an N,N-dimethylformamide solution (2.0 ml) of <strong>[5932-27-4]ethyl 1H-pyrazole-3-carboxylate</strong> (111 mg, 0.79 mmol), sodium hydride (60percent in oil, 70 mg, 1.75 mmol) was added under ice-cooling. The resulting mixture was stirred for 5 min. To the reaction mixture, an N,N-dimethylformamide solution (5.0 ml) of compound 26 (815 mg, 1.71 mmol) and tetrabutylammonium iodide (209 mg, 0.56 mmol) were added. While warming to room temperature, the resulting mixture was stirred for 14 h. The reaction mixture was concentrated in vacuo. To the residue, diethyl ether and distilled water were added. The organic layer was separated and dried over Na2SO4. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol-dichloromethane = 1:100) to give the title compounds, 3-isomer (92 mg, 0.18 mmol, 10percent) and 5-isomer (78 mg, 0.15 mmol, 9percent), respectively. 3-isomer: MS (ESI) m/z 522 (M+H)+. 1H NMR (CDCl3) delta 1.38 (3H, t, J = 7.1 Hz), 2.56-2.69 (2H, m), 3.43 (3H, s), 3.86 (3H, s), 4.28-4.34 (1H, m), 4.38 (2H, q, J = 7.1 Hz), 4.43-4.63 (2H, m), 5.74 (1H, s), 6.27-6.32 (1H, m), 6.35-6.38 (1H, m), 6.71-6.77 (2H, m), 6.97 (1H, dd, J = 8.1, 1.5 Hz), 7.07-7.10 (1H, m), 7.21 (1H, t, J = 8.0 Hz), 7.29-7.39 (3H, m), 7.44 (1H, d, J = 2.2 Hz). 5-isomer: MS (ESI) m/z 522 (M+H)+. 1H NMR (CDCl3) delta 1.33 (3H, t, J = 7.1 Hz), 2.48-2.67 (2H, m), 3.43 (3H, s), 3.85 (3H, s), 4.30 (2H, q, J = 7.1 Hz), 4.38-4.46 (1H, m), 4.81-4.90 (2H, m), 5.72 (1H, s), 6.31-6.40 (2H, m), 6.73 (1H, d, J = 2.2 Hz), 6.81 (1H, d, J = 2.0 Hz), 6.95 (1H, dd, J = 8.1, 1.2 Hz), 7.08 (1H, t, J = 2.1 Hz), 7.19 (1H, t, J = 8.1 Hz), 7.28-7.38 (2H, m), 7.40-7.46 (2H, m).
With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; potassium carbonate; In toluene; at 90℃;
<strong>[5932-27-4]1H-<strong>[5932-27-4]pyrazole-3-carboxylic acid ethyl ester</strong></strong> (0.1 g), 3-bromonaphthalene-1-carbonitrile (0.17 g), copper iodide (0.0068 g), (1R, 2R)-(-)- N, N'-dimethylcyclohexane-1, 2-diamine (0.010 g) and potassium carbonate (0.21 g) in toluene (3 mL) was stirred at 90°C overnight. After cooling to room temperature, ethyl acetate was added to the reaction mixture. The resulting mixture was filtered through a Celite pad. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=100/0-66/34) to give 1-(4-cyanonaphthalene-2-yl)-<strong>[5932-27-4]1H-<strong>[5932-27-4]pyrazole-3-carboxylic acid ethyl ester</strong></strong> (0.040 g). To a solution of this compound (0.040 g) in a mixed solvent of tetrahydrofuran (0.2 mL), ethanol (0.08 mL) and water (0.08 mL) was added lithium hydroxide monohydrate (0.017 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/L hydrochloric acid (0.35 mL). The precipitated solid was collected by filtration, washed with water and n-hexane, and dried under reduced pressure to give the title compound (0.026 g).
General procedure: To a suspension of NaH (60percent) (229 mg, 1.91 mmol) in DMF (10 mL) under nitrogen atmosphere a solution of Preparation 21 (660 mg, 1.91 mmol) in DMF (8 mL) was added. The mixture was stirred at room temperature for 30 min and then ethyl 2-bromo-2,2-difluoroacetate (586 muL, 3.81 mmol) in DMF (8 mL) was added and the reaction mixture stirred overnight at r.t. Solvent was removed and the residue was dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulphate and concentrated. The crude was purified according to the General Purification Method to give the desired compound (10percent yield). LRMS: m/z 469 (M+1)+ Retention time: 7.77 min (Method B); Obtained (35percent) from Preparation 172 and iodoethane following the procedure described in Preparation 23, using dioxane as solvent. LRMS: m/z 169 (M+1)+ Retention time: 2.40 min (Method A) 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.38 (t, J=7.23 Hz, 3 H) 1.44 (t, J=7.23 Hz, 3 H) 4.35 (q, J=7.16 Hz, 2 H) 4.61 (q, J=7.29 Hz, 2 H) 6.83 (d, J=1.95 Hz, 1 H) 7.48 (d, J=1.95 Hz, 1 H).
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 12h;
Example 14A2 4-(3-Ethoxycarbonyl-pyrazol- l-yl)-piperidine-l-carboxylic acid tert-butyl ester A mixture of Example 14A1 (1 g, 3.55 mmol), Example 4A (0.498 g, 3.55 mmol) and K2CO3 (1.47 g, 10.67 mmol) in DMF (20 mL) was heated at 70 °C for 12 hours. TLC (Petroleum ether: EtOAc = 4: 1) indicated that the reaction was completed. The reaction mixture was filtered and the filtrate was concentrated in vacuum and the residue was purified by chromatography on silica to give Example 14A2 (0.65 g, 56.5 percent) as a colorless solid.
With pyridine; oxygen; copper diacetate; In dichloromethane; at 20℃; for 16h;Molecular sieve;
To a mixture of compound XLI-1 (3.7 g, 26.6 mmol), compound XLI-2 (10.6 g, 53.4 mmol), Cu(OAc)2 and Py. in dichloromethane (400 mL) was added to powdered 4A molecular sieves. The reaction mixture was flushed with 02 and stirred at room temperature for 16 hours. The mixture was filtered through celite, the filtrated was concentrated, and the residue was purified by column chromatography (PE:EA=10:1) to give compound XLI-3 (4.5 g, yield 57.5percent).
With copper(l) iodide; potassium carbonate; trans-1,2-cyclohexanediamine; In 1,4-dioxane; for 48h;Reflux; Inert atmosphere;
To a mixture of 3-(ethoxycarbonyl)pyrazole (1 g, 7.14 mmol), CuI (1.12 g, 5.88 mmol) and K2CO3 (1.97 g, 14.29 mmol) in dioxane (20 mL) was added 2-bromo-6-methylpyridine (1.02 g, 5.96 mmol) and trans-1,2-cyclohexanediamine (0.68 g, 5.96 mmol). The mixture was heated at reflux under an atmosphere of argon for 48 h, after which it was cooled to room temperature, diluted with ethyl acetate (80 mL) and filtered through a plug of Celite. The filtrate was washed with saturated EDTA aqueous solution (2 * 25 mL) and was then dried with Na2SO4. The solvents were evaporated under reduced pressure, and the residue was purified by column chromatography (silica, CH2Cl2 as eluent) to give desired product 1 (739 mg, 54percent) as a yellow oil. Rf (CH2Cl2-petroleum ether, 98:02) = 0.50. IR (NaCl plates): nu 1738 cm-1 (CO ester). 1H NMR (CDCl3): delta 1.37 (3H, t, J = 6 Hz), 2.51 (3H, s), 4.39 (2H, q, J = 6 Hz), 6.90 (1H, d, J = 3 Hz), 7.04 (1H, d, J = 9 Hz), 7.66 (1H, t, J = 9 Hz), 7.86 (1H, d, J = 9 Hz), 8.57 (1H, d, J = 3 Hz). 13C NMR (CDCl3): delta 14.35 (CH3), 24.2 (CH3), 61.2 (CH2), 109.85 (CH), 110.0 (CH), 121.9 (CH), 128.3 (CH), 138.9 (CH), 145.7 (Cq), 150.3 (Cq), 157.5 (Cq), 162.3 (CO). MS (ESI+): m/z (percent) 270 (49) [M+K]+, 254 (100) [M+Na]+, 232 (36) [M+H]+.
With copper(l) iodide; potassium carbonate; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; In ethyl acetate; at 140℃; for 3h;
A 50 mL of flask was charged with 3.00 g of 4-chloro-3-fluorobenzenebromide (15 mmol), 1.40 g of ethyl 1-H-pyrazole-3-carboxylate (10 mmol), 400 mg of CuI (2.0 mmol), 4.5 g of K2CO3 (3.3 mmol) and 0.9 mL of trans-N,N'-dimethylcyclohexayldiamine (2.0 mmol). The resulting mixture was stirred at 140° C. for 3 h. After the mixture was cooled down to room temperature, it was diluted with 200 mL EtOAc and then was washed with water (2*50 mL), brine (2*50 mL). The organics was dried over MgSO4 and concentrated under reduced pressure. The residued was purified via flash column chromatography on silica gel (0-25percent EtOAc in hexanes) to get the desired product (1.2 g, 50percent).
With copper(l) iodide; potassium carbonate; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; at 140℃; for 3h;
A 50 mL of flask was charged with 2.87 g of 4-chlorobenzenebromide (15 mmol), 1.40 g of ethyl 1-H-pyrazole-3-carboxylate (10 mmol), 400 mg of CuI (2.0 mmol), 4.5 g of K2CO3 (3.3 mmol) and 0.9 mL of trans-N,N'-dimethylcyclohexayldiamine (2.0 mmol). The resulting mixture was stirred at 140° C. for 3 h. After the mixture was cooled down to room temperature, it was diluted with 200 mL EtOAc and then was washed with water (2*50 mL) and brine (2*50 mL). The organics were dried over MgSO4 and concentrated under reduced pressure. The residued was purified via flash column chromatography on silica gel (0-25percent EtOAc in hexanes) to get the desired product (1.25 g, 50percent).
With copper(l) iodide; potassium carbonate; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; at 140℃; for 3h;
A 50 mL of flask was charged with 2.62 g of 3-fluorobenzenebromide (15 mmol), 1.40 g of ethyl 1-H-pyrazole-3-carboxylate (10 mmol), 400 mg of CuI (2.0 mmol), 4.5 g of K2CO3 (3.3 mmol) and 0.9 mL of trans-N,N'-dimethylcyclohexayldiamine (2.0 mmol). The resulting mixture was stirred at 140° C. for 3 h. After the mixture was cooled down to room temperature, it was diluted with 200 mL EtOAc and then was washed with water (2*50 mL), and brine (2*50 mL). The organics were dried over MgSO4 and concentrated under reduced pressure. The residue was purified via flash column chromatography on silica gel (0-25percent EtOAc in hexanes) to give the desired product (1.17 g, 50percent).
With copper(l) iodide; potassium carbonate; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; In toluene; at 110℃; for 2h;
To a solution of 1-fluoro-4-iodo-benzene (1.47 g, 6.6 mmol, 1.3 eq) and <strong>[5932-27-4]ethyl 1H-pyrazole-3-carboxylate</strong> (0.71 g, 5.1 mmol, 1 eq) in 15 mL of toluene was added CuI (0.19 g, 1.0 mmol, 0.2 eq), trans-N,-N-dimethylcyclohexane 1,2-diamine (0.4 mL, 2.5 mmol, 0.2 eq), and potassium carbonate (1.4 g, 10 mmol, 2 eq). The reaction mixture was heated at 110° C. for 2 d then filtered and concentrated. The residue was purified by silica gel column chromatography (hex:EtoAc 4:1) to afford ethyl 1-(4-fluorophenyl)pyrazole-3-carboxylate (0.92 g, 3.9 mmol, 77percent).
With copper(l) iodide; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; at 140℃; for 3h;
A flask was charged with 2-iodotoluene (0.964mL, 7.57 mmol), <strong>[5932-27-4]ethyl-1H-pyrazole-3-carboxylate</strong> (1.00 g,7.14 mmol), Cul (272 mg, 1.43 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.451 mL, 2.86 mmol), and K2CO3 (3.15 g, 22.8 mmol). The reaction mixture was then heated to 140° C. for 3 h. The reaction was then partitioned between CH2C12 and saturated aqueous NH4C1 and separated.The organic layer was washed with water, dried over Na2SO4, filtered and concentrated. The crude was purified via flash chromatography on silica gel (90:10-70:30 hexanes:methyl tert-butyl ether) to give the product (238 mg, 1.03mmol, 14percent) as a colorless oil.
With potassium carbonate; In N,N-dimethyl-formamide; at 25℃; for 12h;
A mixture of E15 (200 mg, 0.45 mmol), K2C03 (188 mg, 1.36 mmol), ethyl lH-pyrazole-3- carboxylate (317 mg, 2.27 mmol) and DMF (2 mL) were was stirred at 25 °C for 12 hours. TLC showed the reaction was finished. The mixture was diluted with EtOAc (20 mL), washed with brine (30mL*3), and the organic layer was dried over anhydrous Na2S04, and then concentrated to give crude product. It was purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to give the 92 (96 mg, 44.4 percent) as a white solid. 1H NMR (92): (400 MHz, CDC13) delta 7.42 (d, J=2.4 Hz, 1H), 6.86 (d, J=2.4 Hz, 1H), 5.05-4.95 (m, 2H), 4.39 (q, J=7.2Hz, 2H), 4.20-4.10 (m, 1H), 3.49-3.39 (m, 2H), 3.28 (s, 3H) ,2.60-2.55 (m, 1H), 2.22 -1.91 (m, 3H), 1.75-1.50 (m, 6H), 1.45-1.10 (m, 15H), 1.05-0.92 (m, 1H), 0.90-0.84 (m, 1H), 0.70 (s, 3H)
With trifluoroacetic acid; In toluene; at 80℃; for 2h;
To a solution of <strong>[5932-27-4]ethyl 1H-pyrazole-3-carboxylate</strong> (1.80 g, 12.8 mmol) in toluene (12 mL) were added 3,4-dihydro-2H-pyran (1.13 mL, 13.5 mmol) and TFA (14 muL, 128 mumol) and the mixture was stirred at 80° C. for 2 h. The volatiles were removed under reduced pressure and the residue was dissolved in EtOAc and was washed with aqueous Na2CO3 and brine. The organic layer was dried and the volatiles were removed under reduced pressure to give the desired compound which was used in the next step without further purification (2.6 g, 90percent).
N-(6-bromoimidazo[1,2-a]pyrazin-2-yl)cyclopropanecarboxamide[ No CAS ]
[ 5932-27-4 ]
ethyl 1-(2-(cyclopropanecarboxamido)imidazo[1,2-a]pyrazin-6-yl)-1H-pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15.38 g
With copper(l) iodide; potassium carbonate; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; In N,N-dimethyl-formamide; at 130℃;Inert atmosphere;
Combined N-(6-bromoimidazo[l,2-a]pyrazin-2-yl)cyclopropanecarboxamide (12.7 g, 45.2 mmol), ethyl lH-pyrazole-3-carboxylate (9.50 g, 67.8 mmol), (1S,2S)-N1,N2- dimethylcyclohexane-l,2-diamine (1.285 g, 9.04 mmol), copper (I) iodide (1.721 g, 9.04 mmol) and potassium carbonate (15.61 g, 113 mmol) in DMF (Volume: 156 ml). The reaction mixture was purged with nitrogen, capped, and heated at 130°C. After 48 hours additional (l S,2S)-Nl,N2-dimethylcyclohexane-l,2-diamine (1.285 g, 9.04 mmol) and copper (I) iodide (1.721 g, 9.04 mmol) were added. After stirring overnight, the reaction mixture was cooled to room temperature and the DMF was mostly removed via rotovap and then dried under vaccum to give ethyl l-(2-(cyclopropanecarboxamido)imidazo[l,2- a]pyrazin-6-yl)-lH-pyrazole-3-carboxylate (15.38g) which was used without further purification.
1-(4-hydroxypiperidin-1-yl)-3-methylbutan-1-one[ No CAS ]
[ 5932-27-4 ]
ethyl 1-(1-(3-methylbutanoyl)piperidin-4-yl)-1H-pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With cyanomethylenetributyl-phosphorane; In toluene; at 85℃;
Example 409B ethyl 1-(1-(3-methylbutanoyl)piperidin-4-yl)-1H-pyrazole-3-carboxylate (5589) A solution of 1-(hydroxypiperidin-1-yl)-3-methylbutan-1-one (793 mg, 4.28 mmol), <strong>[5932-27-4]ethyl 1H-pyrazole-4-carboxylate</strong> (500 mg, 3.57 mmol) and cyanomethylenetributylphosphorane (1.03 g, 4.28 mmol) in toluene (20 ml) was stirred overnight at 85° C. The solvent was removed and the crude mixture was purified by normal phase chromatography to give the title compound.
1-(2-ethoxy-2-oxoethyl)-1H-pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In acetone; at 60℃;Reflux;
To solution of ethanol (50 mL) and 3-pyrazolecarboxylicacid (1.112 g 10 mmol) at 80 °C was added concentratedsulfuric acid (2 mL), and after 2 h of stirring the<strong>[5932-27-4]ethyl 1H-pyrazole-3-carboxylate</strong> was obtained (1.350 g,9.6 mmol, 96 percent). To 20 mL three-necked round bottomedflask equipped with a refluxing condenser wasadded 1H-pyrazole-3-carboxylate (0.7 g, 5 mmol), ethylbromoacetate (0.835 g, 0.6 mmol) in 30 mL anhydrousacetone. This suspension was stirred at 60 °C and thereaction was monitored by TLC. When the 1H-pyrazole-3-carboxylate was consumed, the yellow brown reactionmixture was concentrated to dryness. The crude productwas purified by column chromatography on silica gelwith petroleum ether/ethyl acetate (1/1) as eluent to givethe liquid state product Eopzc in yield of 55 percent (0.622 g,2.7 mmol). 1H NMR (DMSO-d6, 400 MHz): delta 7.60 (d,J = 2 Hz, 1H), 6.92 (d, J = 2 Hz, 1H), 5.29 (s, 2H), 4.28?4.22 (m, 2H), 4.15?4.10 (m, 2H), 1.27?1.24 (m, 3H),1.20?1.16 (m, 3H); 13C NMR (DMSO-d6, 100 MHz):168.29, 159.50, 139.01, 132.95, 111.87, 61.55, 61.48,53.77, 14.44, 14.40.
ethyl 1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
To a cold solution of ethyl lH-pyrazole-3-carboxylate (1 equiv.) in THF at 0 °C, was added sodium hydride [60 wtpercent disperion on mineral oil] (1 equiv.). The mixture was stirred at 0 °C for 15 min. To this mixture, was added 2-fluorobenzyl bromide (1 equiv.). The mixture was stirred at rt for 2 h. The mixture was diluted in ethyl acetate (100 ml) and washed with water (50 ml). The organic layer was dried, filtered and evaporated to give an oil. The oil was purified by column chromatography (0 to 30percent ethyl acetate in hexanes) to give ethyl l-(2-fluorobenzyl)-lH-pyrazole-3-carboxylate (1.5 g, 85percent yield) as a clear oil. NMR (500 MHz, CHLOROFORM-d) delta ppm 7.44 (d, 1 H) 7.33 - 7.39 (m, 1 H) 7.19 - 7.26 (m, 1H) 7.08 - 7.18 (m, 2 H) 6.85 (d, 1 H) 5.48 (s, 2 H) 4.43 (q, 2 H) 1.42 (t, 3 H)
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