* 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] Journal of the Chemical Society, Chemical Communications, 1985, # 24, p. 1765 - 1766
[2] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3614 - 3622
2
[ 67-56-1 ]
[ 1621-91-6 ]
[ 15366-34-4 ]
Yield
Reaction Conditions
Operation in experiment
79.6%
at 40℃; for 5 h;
To a stirred solution of lH-pyrazole-3-carboxylic acid (2g, 17.8 mmol, 1 eq) in MeOH (20 mL) was added thionyl chloride (2.5mL, 35.5 mmol, 2 eq). The mixture was stirred at 40 °C for 5 h, and then concentrated. The resulting residue was diluted with DCM and washed with saturated aqueous NaHC03 solution. The organic layer was separated, dried and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 1/3, v/v) to give lH-pyrazole-3-carboxylic acid methyl ester (1.8g , 79.6percent) as a white solid.
Reference：
[1] Journal of Medicinal Chemistry, 2008, vol. 51, # 1, p. 159 - 166
[2] Russian Journal of General Chemistry, 2011, vol. 81, # 8, p. 1745 - 1746
[3] Patent: WO2018/11628, 2018, A1, . Location in patent: Paragraph 00314
[4] Heterocycles, 1996, vol. 42, # 2, p. 517 - 523
[5] Journal fuer Praktische Chemie (Leipzig), 1935, vol. <2> 143, p. 259,273
[6] Patent: WO2009/51718, 2009, A2, . Location in patent: Page/Page column 40
[7] Patent: WO2012/143599, 2012, A1, . Location in patent: Page/Page column 62
[8] Patent: US2013/190318, 2013, A1, . Location in patent: Paragraph 0101; 0102
[9] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3614 - 3622
3
[ 1621-91-6 ]
[ 15366-34-4 ]
Yield
Reaction Conditions
Operation in experiment
62%
Stage #1: at 0 - 20℃; for 18 h; Stage #2: With sodium hydrogencarbonate In water
Example A18Preparation of intermediate 18: methyl lH-pyrazole-3-carboxylateSulfuric acid (5.8 mL) was added dropwise to a stirred solution of lH-pyrazole-3- carboxylic acid (1 g, 8.92 mmol) in MeOH (65 mL) at 0 °C. After the addition was completed the mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was concentrated in vacuo and the residue was dissolved in water and basified with NaHC03 (aq. sat. solution). The mixture was extracted with AcOEt. The organic layer was separated, dried (MgS04), filtered and the solvents evaporated in vacuo to yield lH-pyrazole-3-carboxylic acid methyl ester (0.7 g, 62percent yield) as a white solid which was used in the next step without further purification.
With N-iodo-succinimide; trifluoroacetic acid In acetonitrile at 20℃; for 3 h;
To a solution of lH-pyrazole-3-carboxylic acid methyl ester (0.5 g, 4.3 mmol, 1.1 eq) and NIS (0.97 g, 3.9 mmol, 1 eq) in CH3CN (15 mL) was added CF3COOH (0.1 mL). The mixture was stirred at rt for 3 h, and then concentrated. The resulting residue was partitioned between EtOAc and 5percent NaHC03. The organic layer was separated, dried over Na2S04, filtrated, and concentrated. The resulting residue was purified by chromatography on a silica gel column to give 4-iodo-lH-pyrazole-3-carboxylic acid methyl ester (0.61g, 61percent).
Reference：
[1] Journal of Medicinal Chemistry, 2008, vol. 51, # 1, p. 159 - 166
[2] Patent: WO2018/11628, 2018, A1, . Location in patent: Paragraph 00315
[3] Russian Chemical Bulletin, 2010, vol. 59, # 8, p. 1549 - 1555
To a stirred solution of lH-pyrazole-3-carboxylic acid (2g, 17.8 mmol, 1 eq) in MeOH (20 mL) was added thionyl chloride (2.5mL, 35.5 mmol, 2 eq). The mixture was stirred at 40 C for 5 h, and then concentrated. The resulting residue was diluted with DCM and washed with saturated aqueous NaHC03 solution. The organic layer was separated, dried and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 1/3, v/v) to give lH-pyrazole-3-carboxylic acid methyl ester (1.8g , 79.6%) as a white solid.
sulfuric acid; for 12h;Heating / reflux;
Example 10; Synthesis of (lR)-l-(l-naphthyI)-7V-({l-[4-(trifluoromethyl)phenyl]-lH-pyrazol-3- yl}methyl)ethanamineStep 1. A 500 mL round-bottomed flask was charged with l//-pyrazole-3-carboxylic acid 59 (5.0 g, 45 mmol), 100 mL of MeOH, and 10 drops of concentrated sulfuric acid. This mixture was heated to reflux and heating was continued for 12 h. After cooling to room temperature, the solvent was removed and the residue was dissolved in EtOAc and saturated aqueous NaHCO3. The layers were separated and the organic layer was dried and concentrated to give methyl lH-pyrazole-3-carboxylate 60.
With sulfuric acid; for 12h;Reflux;
b) Methyl lH-pyrazole-3-carboxylate lH-Pyrazole-3-carboxylic acid (15 g, 133.8 mmol) was dissolved in MeOH (250 ml). Concentrated H2S04 (30 ml) was added to the solution. The resulting mixture was refluxed for 12 h and concentrated. The residue obtained was quenched by saturated aqueous solution of NaHC03 and extracted with EtOAc. The organic layer was concentrated. Yield 12.05 g. 1H-NMR (400 MHz; CDC13): delta 3.98 (s, 3H), 6.86 (d, 1H), 7.85 (d, 1H), 1 1.9 (bs, 1H).
With sulfuric acid; at 0 - 20℃; for 18h;
Sulfuric acid (5.8 mL) was added dropwise to a stirred solution of 1H-pyrazole-3-carboxylic acid (1 g, 8.92 mmol) in MeOH (65 mL) at 0 C. After the addition was completed the mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was concentrated in vacuo and the residue was dissolved in water and basified with NaHCO3 (aq. sat. solution). The mixture was extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield 1H-pyrazole-3-carboxylic acid methyl ester (0.7 g, 62% yield) as a white solid which was used in the next step without further purification.
With N-iodo-succinimide; trifluoroacetic acid; In acetonitrile; at 20℃; for 3h;
To a solution of lH-pyrazole-3-carboxylic acid methyl ester (0.5 g, 4.3 mmol, 1.1 eq) and NIS (0.97 g, 3.9 mmol, 1 eq) in CH3CN (15 mL) was added CF3COOH (0.1 mL). The mixture was stirred at rt for 3 h, and then concentrated. The resulting residue was partitioned between EtOAc and 5% NaHC03. The organic layer was separated, dried over Na2S04, filtrated, and concentrated. The resulting residue was purified by chromatography on a silica gel column to give 4-iodo-lH-pyrazole-3-carboxylic acid methyl ester (0.61g, 61%).
D. t-butyl (S)-5-(3-methoxycarbonyl-1H-pyrazol-1-yl)-2-(t-butoxycarbonylamino)pentanoate To a solution of <strong>[15366-34-4]methyl 1H-pyrazole 3-carboxylate</strong> (Synth. Comm., 25, 1995, 761) (0.98 g, 7.74 mmol) in DMF (20 ML) at 0 C. is added NaH (60% suspension, 0.31 g, 7.74 mmol) portionwise, over 10 minutes.. After stirring an additional 10 minutes, a solution of t-butyl (S)-5-iodo-2-(t-butoxy-carbonylamino)-pentanoate (2.78 g, 9.29 mmol) in DMF (20 ML) is added over 2 minutes, and the solution is warmed to room temperature over 16 hours.. The solvent is evaporated (high-vac), the residue is treated with water (50 ML) and the aqueous layer is extracted with EtOAc (3*80 ML).. The combined organic layers are washed with water (2*200 ML) and brine (100 ML), dried over MgSO4, and evaporated.. Chromatography (silica, 25% EtOAc/hexane) yields the two regioisomeric products in a 2:1 ratio.. The minor product, which is determined to be the desired product, t-butyl (S)-5-(3-methoxycarbonyl-1H-pyrazol-1-yl)-2-(t-butoxycarbonylamino)-pentanoate, is isolated as a thick, clear oil.
A suspension of 60 % dispersion of sodium hydride in mineral oil (192 mg, 4.8 mmol) in 20 mL of N,N-dimethylformamide was cooled to 0 0C, and methyl 3- pyrazolecarboxylate (605.37 mg, 4.8 mmol) was gradually added with stirring in nitrogen atmosphere. The reaction mixture was stirred at room temperature for 0.5 h and cooled again to 0 C. A solution of 1,1-dimethylethyl 4-[(methylsulfonyl)oxy]-l-piperidine-carboxylate(1.18 g, 4 mmol) (i.e. the product of Example 18, Step A) in 5 mL of N,N- dimethylformamide was gradually added to the reaction mixture. The resulting mixture was stirred for 5 days at 60 C. The reaction mixture was poured in ice water and extracted with ethyl acetate. The organic layer was dried (MgSC^), evaporated in vacuo, and purified by <n="99"/>medium-pressure liquid chromatography on silica gel eluting with 0-10 % methanol in ethyl acetate as eluant to give 290 mg of the title compound as a white solid.1H NMR (CDCl3) delta 1.46 (s, 9H), 1.88-2.00 (m, 2H), 2.12-2.20 (m, 2H), 2.80-2.92 (m, 2H),3.92 (s, 3H), 4.24-4.33 (m, 2H), 4.34-4.37 (m, IH), 6.82 (s, IH), 7.44 (s, IH). Additionally, 370 mg of 1,1-dimethylethyl 4-[5-(methoxycarbonyl)-lH-pyrazol-l-yl]-l- piperidinecarboxylate was isolated eluting before the title compound.1H NMR (CDCl3) 6 1.46 (s, 9H), 1.92-2.00 (m, 2H), 2.08-2.15 (m, 2H), 2.85-2.95 (m, 2H), 3.89 (s, 3H), 4.20-4.31 (m, 2H), 5.24-5.32 (m, IH), 6.85 (s, IH), 7.51 (s, IH).
With potassium phosphate;copper(l) iodide; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; In toluene; at 110℃; for 16h;
Step 2. A 30 mL pressure tube was charged with (1 S,2S)-N ,N2-dimethyl cyclohexane- 1 ,2-diamine 61 (0.41 mL, 2.6 mmol), copper iodide (361 mg, 1.9 mmol), potassium phosphate (6.1 g, 29 mmol), l-iodo-4-(trifluoromethyl)benzene 62 (3.2 g, 12 mmol), methyl lH-pyrazole- 3-carboxylate 60 (1.5 g, 12 mmol), and 15 mL of toluene. This mixture was heated at 1 10C for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc and filtered. The filtrate was concentrated onto silica and purified by flash column chromatography on silica gel (0% to 3% MeOH in DCM) to give methyl l-(4-(trifluoromethyl)phenyl)-l//-pyrazole-3- carboxylate 63.
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).
Methyl 1 H-pyrazole-3-carboxylate (12.61 mg, 0.1 mmol) was dissolved in a 0. 105M solution of potassium tert-butoxide in ethanol (1 ml, 11.78 mg, 0.105 mmol). After stirring at room temperature for 5 mins, a 0. 1 M solution of 4-bromo-2- (bromomethyl) phenyl phenylmethyl ether in ethanol (1 ml, 35.6 mg, 0.1 mmol) was added and the resulting solution was stirred and heated at 60C under nitrogen for 4hrs. After cooling the mixture was diluted with ethanol (1 ml) and a 0.5M solution of lithium hydroxide in water (1 ml, 11.97mg, 0. 5mmol) was added. The mixture was stirred overnight at 40C. After cooling 2M hydrochloric acid (0. 3moi, 0. 6mmol) was added and the mixture was diluted with water. Dichloromethane was added and the mixture stirred vigorously. The organic layer was separated and the solvent removed in vacuo. The residue was purified by mass directed autopurification to yield the title compound. 1-({5-bromo-2-[(phenylmethyl) oxy] phenyl} methyl)-5-methyl-1 H-pyrazole-3-carboxylic acid: (10. 7mg, 27.6%). 'H NMR 8 : 5.08 (2H, s), 5.34 (2H, s), 6.72 (1H, d, J = 2.2Hz), 6.92 (1H, d, J = 8.8Hz), 7.23 (1H, d, J = 2Hz), 7.30-7. 39 (6H, m), 7.45 (1H, d, J = 2Hz). t = 3.38, [MH+] 387, 389 [MH-] 385,387.
Step B: Preparation of 1,1-dimethylethyl 4-[3-(methoxycarbonyl)-1H-pyrazol-1-yl]-1-piperidinecarboxylate. A suspension of 60 % dispersion of sodium hydride in mineral oil (192 mg, 4.8 mmol) in 20 mL of N,N-dimethylformamide was cooled to 0 C, and methyl 3-pyrazolecarboxylate (605.37 mg, 4.8 mmol) was gradually added with stirring in nitrogen atmosphere. The reaction mixture was stirred at room temperature for 0.5 h and cooled again to 0 0C. A solution of 1,1-dimethylethyl 4-[(methylsulfonyl)oxy]-1-piperidine-carboxylate (1.18 g, 4 mmol) (i.e. the product of Example 18, Step A) in 5 mL of N,N- dimethylformamide was gradually added to the reaction mixture. The resulting mixture was stirred for 5 days at 60 0C. The reaction mixture was poured in ice water and extracted with ethyl acetate. The organic layer was dried (MgSO4), evaporated in vacuo, and purified by medium-pressure liquid chromatography on silica gel eluting with 0-10 % methanol in ethyl acetate as eluant to give 290 mg of the title compound as a white solid. 1H NMR (CDCl3) 6 1.46 (s, 9H), 1.88-2.00 (m, 2H), 2.12-2.20 (m, 2H), 2.80-2.92 (m, 2H), 3.92 (s, 3H), 4.24-4.33 (m, 2H), 4.34-4.31 (m, IH), 6.82 (s, IH), 7.44 (s, IH).Additionally, 370 mg of 1,1-dimethylethyl 4-[5-(methoxycarbonyl)-1H-pyrazol-1-yl]-1-piperidinecarboxylate was isolated eluting before the title compound. 1H NMR (CDCl3) 5 1.46 (s, 9H), 1.92-2.00 (m, 2H), 2.08-2.15 (m, 2H), 2.85-2.95 (m, 2H), 3.89 (s, 3H), 4.20-4.31 (m, 2H), 5.24-5.32 (m, IH), 6.85 (s, IH), 7.51 (s, IH).
Example A18Preparation of intermediate 18: methyl lH-pyrazole-3-carboxylateSulfuric acid (5.8 mL) was added dropwise to a stirred solution of lH-pyrazole-3- carboxylic acid (1 g, 8.92 mmol) in MeOH (65 mL) at 0 C. After the addition was completed the mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was concentrated in vacuo and the residue was dissolved in water and basified with NaHC03 (aq. sat. solution). The mixture was extracted with AcOEt. The organic layer was separated, dried (MgS04), filtered and the solvents evaporated in vacuo to yield lH-pyrazole-3-carboxylic acid methyl ester (0.7 g, 62% yield) as a white solid which was used in the next step without further purification.
With sulfuric acid; sodium hydrogencarbonate; In methanol;
b) Methyl 1H-pyrazole-3-carboxylate 1H-Pyrazole-3-carboxylic acid (15 g, 133.8 mmol) was dissolved in MeOH (250 ml). Concentrated H2SO4 (30 ml) was added to the solution. The resulting mixture was refluxed for 12 h and concentrated. The residue obtained was quenched by saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was concentrated. Yield 12.05 g. 1H-NMR (400 MHz; CDCl3): delta 3.98 (s, 3H), 6.86 (d, 1H), 7.85 (d, 1H), 11.9 (bs, 1H).
With pyridine; copper diacetate; In N,N-dimethyl-formamide; at 90℃; for 2h;
Step 1 methyl 1(2,4-dimethoxyphenyl)-1H-pyrazole-3-carboxylate (2) To a solution of 2,4-dimethoxyphenylboronic acid 1 (2.88 g, 15.8 mmol, 1.00 equiv) in DMF (100 mL) was added <strong>[15366-34-4]methyl 1H-pyrazole-3-carboxylate</strong> (3.00 g, 23.7 mmol, 1.50 equiv), Cu(OAc)2 (5.70 g, 31.6 mmol, 2.00 equiv), and pyridine (3.76 g, 47.4 mmol, 3 equiv). The resulting solution was stirred for 2 h at 90 C. The solids were filtrated off by filtration and the filtrate was extracted by EtOAc (200 mL*3). The combined organic layers were dried by anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with PE/EA (3/1). This resulted in 1.5 g (36%) of methyl 1-(2,4-dimethoxyphenyl)-1H-pyrazole-3-carboxylate 2 as a brown solid. 1H NMR (300 MHz, CDCl3): delta 7.88 (d, J=2.4 Hz, 1H), 7.61 (d, J=9 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 6.59 (s, 1H), 7.73, 6.58 (d, J=8.7 Hz, 1H). LC-MS: m/z=263 (MH)+.
Example A19Preparation of intermediate 19: methyl l-(dimethylsulfamoyl)-lH-pyrazole-3- carboxylateSodium hydride (1.57 g, 41.03 mmol) was added to a solution of lH-pyrazole-3- carboxylic acid methyl ester (3.45 g, 27.36 mmol) in THF (20 mL) at 0 C. The mixture was stirred at 0 C for 30 minutes. Then dimethyl sulfamoyl chloride (4.41 mL, 41.03 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was diluted with water and the product extracted with AcOEt. The organic layer was separated, dried (MgS04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; AcOEt in DCM 0/100 to 10/90). The desired fractions were collected and concentrated in vacuo to yield l-dimethylsulfamoyl-lH-pyrazole-3-carboxylic acid methyl ester (4.8 g, 75% yield) as a colourless oil.
75%
Sodium hydride (1.57 g, 41.03 mmol) was added to a solution of <strong>[15366-34-4]1H-pyrazole-3-carboxylic acid methyl ester</strong> (3.45 g, 27.36 mmol) in THF (20 mL) at 0 C. The mixture was stirred at 0 C. for 30 minutes. Then dimethylsulfamoyl chloride (4.41 mL, 41.03 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was diluted with water and the product extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; AcOEt in DCM 0/100 to 10/90). The desired fractions were collected and concentrated in vacuo to yield 1-dimethylsulfamoyl-<strong>[15366-34-4]1H-pyrazole-3-carboxylic acid methyl ester</strong> (4.8 g, 75% yield) as a colourless oil.
With copper(I) oxide; salicylaldehyde-oxime; caesium carbonate; In N,N-dimethyl-formamide; at 110℃; for 48h;
a) Methyl 1 '-methyl- l'H-l,4'-bipyrazole-3-carboxylateInto a solution of methyl lH-pyrazole-3-carboxylate (10 g, 79.3 mmol) in DMF (80 ml), cuprous oxide (0.567 g, 3.96 mmol), salicylaldoxime (1.08 g, 7.93 mmol), Cs2C03 (64.4 g, 198.4 mmol) and 1 -methyl-4-iodo pyrazole (16.5 g, 79.9 mmol) were added and the mixture was stirred at 1 10 C for 48 h. The reaction mixture was quenched with saturated solution of aqueous NaHC03 and extracted with EtOAc. The organic layer was concentrated and purified by flash-chromato- graphy. Yield 2.9 g. IH-NMR (400 MHz; DMSO-d6): delta 3.83 (s, 3H), 3.88 (s, 3H), 7.90 (s, 1H), 8.29 (d, 2H). LC-MS: [M+H] = 207.
With [2,2]bipyridinyl; copper diacetate; sodium carbonate; In 1,2-dichloro-ethane; at 70℃; for 8h;
To a stirred solution of methyl IH-pyrazole-3-carboxylate (1.04 g, 8.25 mmol),cyclopropylboronic acid (1.42g, 16.5 mmol) and Na2CO3 (1.75 g, 16.5 mmol) in DCE (30niL) at 70 C was added 2,2?-bipyridine (1.29 g, 8.25 mmol) and copper (11) acetate (1.50 g,8.25 mmol) under air. The reaction was heated to 70 C for 8 his. The reaction was allowed to cool to RT. 1 mL AcOH was added and the reaction mixture was concentrated in vacuo and the residue diluted with EtOAc. The organic layer was washed with 1M HC1. Theorganic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue wasadded to a silica gel (120 g) column and eluted with 0-100% EtOAc in hexanes. Fractions containing Compound 61a were collected and the solvent removed in vacuo to yield a clear liquid (1.05 g, 6.29 mmol, 76 % yield). MS rn/z 167.1 (M+H). ?HNMR (400 MHz, DMSO-d6) E 7.93 (d, J=2.4 Hz, 1H), 6.73 (d, J?2.4 Hz, 1H), 3.85 (if, J7.4, 3.8 Hz, 1H), 3.78 (s, 3H), 1.13 - 1.06 (m, 2H), 1.06 0.97 (m, 2H).
54%
With 1,10-Phenanthroline; copper diacetate; sodium carbonate; In 1,2-dichloro-ethane; at 70℃; for 4h;
Step 4: To a mixture of methyl 1H-pyrazole-5-carboxylate (3.15 g, 25.0 mmol), cyclopropylboronic acid (4.30 g, 50.0 mmol), sodium carbonate (5.30 g, 50.0 mmol), and dichloroethane (125 mL) at 70 C was added a heated suspension of copper(II) acetate (4.55 g, 25.0 mmol), 1,10-phenanthroline (4.50 g, 25.0 mmol), and dichloroethane (31 mL). The reaction mixture was then stirred vigorously under air at 70 C for 4 hours. The reaction mixture was cooled and filtered through Celite. The solvent was removed and the residue purified by silica gel chromatography (0 to 100% EtOAc in hexanes) to afford the desired product as a pale green
c) Methyl l-cyclopropyl-lH-pyrazole-3-carboxylateMethyl lH-pyrazole-3-carboxylate (4 g, 31.7 mmol) was dissolved in di- chloroethane (160 ml). Na2C03 (6.72 g, 63.4 mmol) and cyclopropylboronic acid (5.44 g, 63.4 mmol) were added to the solution. The resulting mixture was heated to 70 C and a hot solution of bipyridine (4.92 g, 31.6 mmol) and Cu(OAc)2 (5.72 g, 31.6 mmol) in dichloroethane (40 ml) was added. The mixture was stirred at 70 C under an oxygen atmosphere overnight. Saturated aqueous solution of NaHC03 was added to the reaction mixture and extracted with EtOAc. The organic layer was evaporated and the residue was purified by flash chromatography. Yield 2.5 g. - NMR (400 MHz; DMSO-d6): delta 1.04-1.09 (m, 2H), 1.17-1.23 (m, 2H), 3.64-3.69 (m, IH), 3.91 (s, 3H), 6.78 (d, IH), 7.46 (d, IH).
With [2,2]bipyridinyl; sodium hydrogencarbonate;
c) Methyl 1-cyclopropyl-1H-pyrazole-3-carboxylate Methyl 1H-pyrazole-3-carboxylate (4 g, 31.7 mmol) was dissolved in dichloroethane (160 ml). Na2CO3 (6.72 g, 63.4 mmol) and cyclopropylboronic acid (5.44 g, 63.4 mmol) were added to the solution. The resulting mixture was heated to 70 C. and a hot solution of bipyridine (4.92 g, 31.6 mmol) and Cu(OAc)2 (5.72 g, 31.6 mmol) in dichloroethane (40 ml) was added. The mixture was stirred at 70 C. under an oxygen atmosphere overnight. Saturated aqueous solution of NaHCO3 was added to the reaction mixture and extracted with EtOAc. The organic layer was evaporated and the residue was purified by flash chromatography. Yield 2.5 g. 1H-NMR (400 MHz; DMSO-d6): delta 1.04-1.09 (m, 2H), 1.17-1.23 (m, 2H), 3.64-3.69 (m, 1H), 3.91 (s, 3H), 6.78 (d, 1H), 7.46 (d, 1H).
With iron(III) chloride; In nitromethane; at 20℃; for 24h;
Method 75 Synthesis of methyl 4-[1-[4-(2-aminopyrimidin-5-yl)phenyl]cyclobutyl]-1H-pyrrole-3-carboxylate (Example 162) To a solution of I-66.1 (100 mg, 0.41 mmol) in nitromethane (5 mL) is added iron (III) chloride (20.16 mg, 0.12 mmol) and <strong>[15366-34-4]methyl-1H-pyrazole-3-carboxylate</strong> (62.2 mg, 0.497 mmol) and is stirred at room temperature for 24 hours. The reaction is concentrated in vacuo, and the residue is partitioned between saturated aqueous NaHCO3 and EtOAc. The combined organics are dried with Mg2SO4, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, 0-10% MeOH in CH2Cl2) to give the title compound 162 (5 mg).
With caesium carbonate; In N,N-dimethyl-formamide;
a) Methyl 1'-methyl-1'H-1,4'-bipyrazole-3-carboxylate Into a solution of <strong>[15366-34-4]methyl 1H-pyrazole-3-carboxylate</strong> (10 g, 79.3 mmol) in DMF (80 ml), cuprous oxide (0.567 g, 3.96 mmol), salicylaldoxime (1.08 g, 7.93 mmol), Cs2CO3 (64.4 g, 198.4 mmol) and 1-methyl-4-iodo pyrazole (16.5 g, 79.9 mmol) were added and the mixture was stirred at 110 C. for 48 h. The reaction mixture was quenched with saturated solution of aqueous NaHCO3 and extracted with EtOAc. The organic layer was concentrated and purified by flash-chromatography. Yield 2.9 g. 1H-NMR (400 MHz; DMSO-d6): delta 3.83 (s, 3H), 3.88 (s, 3H), 7.90 (s, 1H), 8.29 (d, 2H). LC-MS: [M+H]=207.
a) Methyl 1-(2-methylprop-1-enyl)-1H-pyrazole-3-carboxylate The title compound was prepared using the procedure described in Example 17(a) starting from <strong>[15366-34-4]methyl 1H-pyrazole-3-carboxylate</strong> (8 g, 63.4 mmol) and 1-bromo-2-methyl propene (12.7 g, 95.2 mmol). The product was purified with flash chromatography. Yield 2.4 g. 1H-NMR (400 MHz; CDCl3): delta 1.81 (d, 3H), 1.87 (d, 3H), 3.93 (s, 3H), 6.70 (d, 1H), 6.87 (d, 1H), 7.47 (d, 1H).
With copper(l) iodide; potassium carbonate; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; at 140℃; for 3h;
A 50 mL flask was charged with 1.89 g of startingmaterial 1 (15mmol), 1.96 g of starting material 2 (10 mmol),400 mg of Cul (2.0 mmol), 4.5 gofK 2C 0 3 (3.3 mmol) and 0.9mL of trans-N,N'-dimethylcyclohexayldiamine (2.0 mmol).The resulting mixture was stirred at 140 C. for 3 h. After themixture was cooled down to room temperature, 200 mL ofEtOAc was added and the oiganics were washed with water(2x50 mL), brine (2x50 mL). The oiganics were dried overM gS04 and concentrated under reduced pressure. The residuewas purified via flash chromatography on silica gel(0-25% EtOAc in hexanes) to get the desired product 3 (1.2 g,50%).
With caesium carbonate; In acetonitrile; at 20℃; for 2h;
A solution of <strong>[15366-34-4]methyl 1H-pyrazole-3-carboxylate</strong> (5 g) in dry acetonitrile was treated with cesium carbonate (32.3 g) and methyl iodide (6.45 g) and the mixture was stirred at rt for 2 h. The suspension was filtered and the volatiles were removed under reduced pressure. The residue was purified by chromatography (SiO2, Cy/EtOAc) to yield the desired product (66% yield). LC-MS (Method 1): m/z [M+H]+=141.2 (MW calc.=140.14); Rt=1.0 min.
66%
With caesium carbonate; In acetonitrile; at 20℃; for 2h;
Intermediate 15a) A solution of methyl 1 /-/-pyrazole-3-carboxylate (5 g) in dry acetonitrile was treated with cesium carbonate (32.3 g) and methyl iodide (6.45 g) and the mixture was stirred at rt for 2 h. The suspension was filtered and the volatiles were removed under reduced pressure. The residue was purified by chromatography (Si02, Cy /EtOAc) to yield the desired product (66% yield). LC-MS (Method 1): mlz [M+H]+ = 141.2 (MW calc. = 140.14); R, = 1.0 min.
Sodium hydride (252 mg, 10.5 mmol) was added to a solution of methyl 1H-pyrazole-3- carboxylate (883 mg, 7.00 mmol) in NMP (17.5 mL) in a microwave vial. The reaction was stirred at room temperature for 0.5 hours. tert-Butyl 4-((methylsulphonyl)oxy)-piperidine-1-carboxylate (1955 mg, 7 mmol) was added and the vial sealed. The reaction was heated to 75C overnight. The reaction mixture was partitioned between DCM and water, dried (hydrophobic frit) and the organic phase concentrated in vacuo. The crude product was purified by reverse phase chromatography on C18 silica eluted with 5-95% water (with 0.05% ammonia)/acetonitrile to afford tert-butyl 4-(5-(methoxycarbonyl)- 1H-pyrazol-1-yl)piperidine-1-carboxylate (337 mg, 1.089 mmol, 15.6 %)?H NMR (400 MHz, DMSO-d6) & 1.41 (s, 9 H) 1.71 - 1.96 (m, 4 H) 3.19 - 3.37 (m, 2 H)3.84 (s, 3 H) 4.07 (m, J=12.60 Hz, 2 H) 5.11 - 5.30 (m, 1 H) 6.89 (d, J=2.02 Hz, 1 H) 7.61(d, J=1.77 Hz, 1 H)
methyl 1-[[4-(methoxycarbonyl)-2-nitrophenyl]methyl]-1H-pyrazole-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
23%
With potassium carbonate; In acetonitrile; at 0 - 25℃;Inert atmosphere;
1-[[4-(methoxycarbonyl)-2-nitrophenyl]methyl]-1H-pyrazole-5-carboxylateInto a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed potassium carbonate (11.2 g, 80.45 mmol, 2.00 equiv), methyl 1H-pyrazole-5-carboxylate (5.08 g, 40.28 mmol, 1.00 equiv)(Example 557) and acetonitrile (100 mL) with stirring at 0 C. This was followed by the addition of a solution of <strong>[88089-94-5]methyl 4-(bromomethyl)-3-nitrobenzoate</strong> (11 g, 40.14 mmol, 1.00 equiv) in acetonitrile (100 mL) dropwise with stirring at 0 C. in 5 min. The resulted solution was stirred overnight at 25 C. The mixture was concentrated under vacuum. The crude product was purified by flash column chromatography eluted with ethyl acetate/petroleum ether (1:10-1:0). This resulted in 3.00 g (23%) of methyl 1-[[4-(methoxycarbonyl)-2-nitrophenyl]methyl]-1H-pyrazole-5-carboxylate as white solid. The crude product was used in the next step without further purification.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 40h;
Step 1: Methyl 1H-pyrazole-3-carboxylate (2.52 g, 20 mmol, 1 equiv.) was dissolved in DMF (20 mL). K2CO3 (5.53 g, 40 mmol, 2 equiv.) was added, followed by 1-chloro-2-methyl- 2-propanol (2.67 mL, 26 mmol, 1.3 equiv.). The reaction mixture was heated to 80 °C for 40 hours and cooled to room temperature. The reaction mixture was poured into water, extracted with EtOAc, and the combined organic extracts were washed with water and brine. The organic layer was concentrated, and the crude residue was purified on SiO2 (25 100percent EtOAc/Hexanes) to afford the title compound as a colorless oil that solidified upon standing (2.08 g, 53percent yield).
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