* 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.
Synthesis of /V-((2-hydroxy-4,( methyl-l-(l-benz\rl)-l /-pyrazoie-4-carboxamide (Compound 11 esis 14] To a solution of 3-methyi-lH-pyrazole-4-carboxylic acid (1.26 g, 10 mmol) in methanol (100 mL) was added thionyl chloride (5.73 g, 45 mmol) at 0 °C. The mixture was stirred for 12 hours. The solvent was evaporated in vacuo. To the residue, saturated sodium bicarbonate aqueous solution was added and the mixture was extracted with ethyl acetate (100 mLx 3), the organic phase was dried by sodium, sulfate. The mixture was filtered and the filtrate was concentrated in vacuo to give methyl 3-m.ethyl-lH~pyrazole~4~carboxylate (0.8 g, 57percent). H NMR (300 MHz, CDCI3): δ 7.87 (s, 1H), 3.84 (s, 3H), 2.53 (s, 3H).
57%
at 0℃; for 12 h;
Methyl5-methyl-1H-pyrazole-4-carboxylate. To a solution of 3-methyl-1H-pyrazole-4-carboxylic acid (1.26 g, 10 mmol) in MeOH (100 mL) was added thionyl chloride (5.73 g, 48 mmol) at 0 °C. The mixture was stirred for 12 h and then concentrated in vacuo. The residue was quenched with sat. aq. sodium bicarbonate solution and extracted with EtOAc (3X). The combined organic phase was dried over sodium sulfate, filtered and concentrated to provide methyl 3-methyl-1H-pyrazole-4-carboxylate (0.8 g, 57percent).
Reference:
[1] Patent: WO2013/120104, 2013, A2, . Location in patent: Paragraph 00183; 00184
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 17, p. 3644 - 3649
[3] Advanced Synthesis and Catalysis, 2010, vol. 352, # 11-12, p. 2041 - 2049
3-semicarbazono-butyric acid methyl ester[ No CAS ]
[ 3724-43-4 ]
[ 23170-45-8 ]
Yield
Reaction Conditions
Operation in experiment
In dichloromethane; at 70℃;
A mixture of methyl (3E)-3-[(aminocarbonyl)hydrazono]butanoate (5-2) (14.0 g, 80.8 mmol, 1 equiv) and (chloromethylene)dimethyliminium chloride (51.0 g, 457 mmol, 1.06 equiv) in dichloromethane (100 mL) was heated at 70 C with dichloromethane distilling off overnight. The residual oil was diluted with saturated aqueous sodium acetate (100 mL) and the solution was extracted with chloroform (2 x 200 mL). The combined organic extracts were dried over sodium sulfate and concentrated to yield methyl 3-methyl-1H-pyrazole-4-carboxylate (5-3) as an orange gum. LRMS m/z (M+H) 140.9 found, 141.1 required.
3 -methyl- 1H-pyrazole-4-carboxylic acid (5-4)A mixture of methyl 3-methyl-1H-pyrazole-4-carboxylate (5-3) (11.3 g, 80.6 mmol, 1 equiv) and sodium hydroxide (7.00 g, 175 mmol, 2.17 equiv) in water (100 mL) and acetonitrile (20 mL) was stirred at 65 C for 5 h. The solution was cooled, acidified to pH 3-4 with concentrated hydrochloric acid solution and extracted with ethyl acetate (3 x 250 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to yield 3-methyl-1H-pyrazole-4-carboxylic acid (5-4) as a yellow solid. LRMS m/z (M+H) 126.7 found, 127.0 required.
methyl l-isopropyl-5(3)-methyl-lH-pyrazole-4-carboxylateDissolve methyl 3 -methyl- lH-pyrazole-4-carboxy late (2.375g, 16.95 mmol) in DMF (85 mL), sodium hydride (0.471 g, 18.64 mmol) (95% in mineral oil) was added portion wise under nitrogen. The reaction was stirred for approximately 10 minutes and 2-iodopropane (1.861 mL, 18.64 mmol) was added to the reaction. The reaction was stirred at room temperature under a nitrogen atmosphere overnight (23hr). Solvent was removed from the reaction in vacuuo using a rotary evaporator. The orange residue was partitioned between 1.0N aqueous hydrochloric acid (~30ml) and ethyl acetate. The yellow colored aqueous solution was extracted with ethyl acetate and the organic extracts were combined and washed Ix with saturated aqueous sodium bicarbonate solution. The aqueous hydrochloric acid washes were neutralized to pH of ~4 with ION aqueous sodium hydroxide then saturated aqueous sodium bicarbonate added to make the solution basic. The basic aqueous solutions were combined and extracted with ethyl acetate. The organic extracts were combined and washed with brine and dried over magnesium sulfate, filtered and solvent removed in vacuuo to yield a yellow oil (4.4g). The yellow oil was dissolved in benzene and volatiles removed in vacuuo using a rotary evaporator (bath temp= 40C) to obtain a yellow oil (weight= 2.964g). The material was dissolved in a small amount of dichloromethane and applied to a silica gel column (105g) slurry loaded in dichloromethane. The product was eluted with dichloromethane to yield a mixture of isomers as a yellow oil (1.736g).IH NMR (500 MHz, CHLOROFORM-D) delta ppm 1.46 (s, 2.29 H) 1.47 (s, 5.08 H) 1.48 (s, 3.03 H) 2.45 (s, 3.00 H) 2.54 (s, 1.99 H) 3.79 (s, 3.15 H) 3.79 (s, 1.91 H) 4.34 - 4.49 (m, 1.80 H) 7.83 (s, 1.02 H) 7.85 (s, 0.65 H).
Synthesis of /V-((2-hydroxy-4,( methyl-l-(l-benzrl)-l /-pyrazoie-4-carboxamide (Compound 11 esis 14] To a solution of 3-methyi-lH-pyrazole-4-carboxylic acid (1.26 g, 10 mmol) in methanol (100 mL) was added thionyl chloride (5.73 g, 45 mmol) at 0 C. The mixture was stirred for 12 hours. The solvent was evaporated in vacuo. To the residue, saturated sodium bicarbonate aqueous solution was added and the mixture was extracted with ethyl acetate (100 mLx 3), the organic phase was dried by sodium, sulfate. The mixture was filtered and the filtrate was concentrated in vacuo to give methyl 3-m.ethyl-lH~pyrazole~4~carboxylate (0.8 g, 57%). H NMR (300 MHz, CDCI3): delta 7.87 (s, 1H), 3.84 (s, 3H), 2.53 (s, 3H).
57%
With thionyl chloride; at 0℃; for 12h;
Methyl5-methyl-1H-pyrazole-4-carboxylate. To a solution of <strong>[40704-11-8]3-methyl-1H-pyrazole-4-carboxylic acid</strong> (1.26 g, 10 mmol) in MeOH (100 mL) was added thionyl chloride (5.73 g, 48 mmol) at 0 C. The mixture was stirred for 12 h and then concentrated in vacuo. The residue was quenched with sat. aq. sodium bicarbonate solution and extracted with EtOAc (3X). The combined organic phase was dried over sodium sulfate, filtered and concentrated to provide methyl 3-methyl-1H-pyrazole-4-carboxylate (0.8 g, 57%).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;
Synthesis of methyl l-benzyl-S-methyl-lH^yrazole-4-carboxylate. [00186] To a solution of methyl 3-methyl-lH-pyrazole-4-carboxylate (280 mg, 2 mmol) in N, N-dimethylformamide (30 mL) was added (bromomethyl)benzene (0.34 g, 2 mmol) and potassium carbonate (0.55 g, 4 mmol). The mixture was stirred at 20 C and stirred for 12 hours. The solvent was evaporated in vacuo and the residue was purified by CXTH (Column:Dsisol, 10muMu, CI 8, 250 mm*50 mm; Mobile: aeetonitrile(0.1% formic acidj-water (0.1% formic acid), acetonitrile from 30% to 70% in 80 minutes; oven; 20C; flow rate: 50 mL/minute, wavelength; 214 nm) to give crude methyl 1 -benzyl-5-meth.yl- lH-pyrazole-4-earboxylate (200 mg, 42%). LRMS (M + H+) m/z calcd. 230.1 1 ; found 230.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;
Synthesis of methyl 5-methyl-l-phenethyl~lH-pyrazole~4-carboxylate. [00193] To a solution of methyl 3-methyl-lH-pyrazole-4-carboxylate (280 mg, 2 mmol) in N,N-dimethylformamide (30 mL) was added (bromoethyl)benzene (0.37 g, 2 mmol) and potassium carbonate (0.55 g, 4 mmol). The mixture was stirred at 20 C for 12 hours. The solvent was evaporated in vacuo and the residue was purified by CXTH (CoIumnrDsisoI, 10muMu, C18, 250 mm*50 mm; Mobile: acetonitrile (0.1% formic acid) - water (0.1% formic acid), acetonitriie from 30% to 70% in 80 minutes; oven: 20 "C; flow rate: 50 mL/minute, wavelength: 214 nm) to give crade methyl 5-methyl-l-phenethyl-lH-pyrazole-4-carboxylate ( 177 mg, 36%). The product was used for the next step directly. LRMS (M + tT) m/z calcd. 244.12; found 244
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;
Methyl 3-methyl-1-(1-phenylethyl)-1H-pyrazole-4-carboxylate. To a solution of <strong>[23170-45-8]methyl 3-methyl-1H-pyrazole-4-carboxylate</strong> (280 mg, 2 mmol) in DMF (30 mL) was added (1-bromoethyl)benzene (0.37 g, 2 mmol) and potassium carbonate (0.55 g, 4 mmol). The mixture was stirred at 20 C and stirred for 12 h. The solvent was evaporated in vacuo and the residue was purified by HPLC (Column: Dsisol, 10mu, C18, 250 mm x 50 mm; Mobile: acetonitrile (0.1% formic acid)-water (0.1% formic acid), acetonitrile from 30 to 70 in 80 minutes; oven: 20 C; flow rate: 50 mL/minute, wavelength: 214 nm) to give methyl 3-methyl-1-(1-phenylethyl)-1H-pyrazole-4-carboxylate (90 mg, 19%, desired) and methyl 5-methyl-1-(1-phenylethyl)-1H-pyrazole-4-carboxylate (80 mg, 16%). The product was used for the next step directly.
Step 1 : Methyl 3-oxobutanoate (8 g, 1.0 eq.) and l,l-dimethoxy-N,N- dimethylmethanamine (DMFDMA) (9.8 g, 1.2 eq.) were combined in a 100 mL flask. The mixture was heated at 100 C for 4 h. The mixture was cooled to room temperature and diluted with EtOH (40 mL). To this solution was added dropwise hydrazine hydrate (4.2 g, 1.2 eq). The resulting mixture was heated at refluxing overnight. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (50 mL), washed with water (3 x 30 mL) and brine, and concentrated to afford crude compound 13 (8.6 g, 88%) which was used without further purification.
With bromine; sodium acetate; In acetic acid; at 100℃; for 3h;Sealed tube;
Step 2: To a solution of compound 13 (8.6 g, 1.0 eq.) in acetic acid (50 mL) was added sodium acetate (15.1 g, 3 eq.). To the suspended solution was added Br2 (29.5 g, 3 eq.) dropwise. The resulting mixture was stirred at room temperature for 10 minutes, and then heated at 100 C in a sealed-tube for 3 h. The solvent and excess Br2 was removed in vacuo. The residue was diluted with ethyl acetate (100 mL), washed with water (2 x 30 mL), saturated NaHC03, and brine. The organic phase was dried over Na2S04, and concentrated in vacuo to afford a yellow oil (13.5 g). The oil was dissolved in ethyl acetate (40 mL) and hexane (100 mL) was added. The precipitated yellow solid was collected by filtration, washed with hexane and dried to afford 14 (9.8 g, 72.8%) which was used without further purification.
1-(3'-nitro-4'-piperidinophenyl)-3-methyl-pyrazole-4-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58.1%
With copper(l) iodide; trans-N1,N2-dimethylcyclohexane-1,2-diamine; potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 24h;Inert atmosphere;
N2 protection,3-methyl-1H-pyrazole-4-carboxylate(0.14 g, 1.0 mmol), CuI (19.1 mg,0.1 mmol), K2CO3 (0.29 g, 2.1 mmol)III3 (0.34 g, 1.2 mmol),(E) -N, N'-dimethyl-1,2-cyclohexyl diamine (28.5 mg, 0.2 mmol) and DMF (3 mL) were added to a 25 mL two-necked flask and reacted at 110 C for 24 h,Cooled to room temperature, diluted with 10 mL of water, extracted with ethyl acetate (15 mL x 3)Saturated brine (10 mL), dried over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure,Silica gel column (V ethyl acetate: V petroleum ether = 6: 1),To a solution of 0.2 g of methyl orange 1- (3'-nitro-4'-piperidine-phenyl) -3-methyl-pyrazole-4-carboxylate (IV3).
58%
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 24h;Inert atmosphere;
General procedure: Compound (11a-g or 12f-g) (1.2 mmol), CuI (19.1 mg, 0.1 mmol), trans-N,N'-dimethyl-1,2-cyclohexane-diamine (29 mg, 0.2 mmol), K2CO3 (0.29 g, 2.1 mmol) and DMF (3 mL) were added to a tube filled with argon. The mixture was stirred at 110 C for 24 h. The reaction was diluted with H2O (20 mL) and extracted with EtOAc (15 mL x 2). The combined organic phases were washed with H2O (20 mL x 2) and brine (30 mL), dried over MgSO4 and concentratedin a vacuum. The residue was purified by flash column chromatography (12-25% EtOAc in petroleum ether).
1-(3'-cyano-4'-morpholinophenyl)-3-methyl-pyrazole-4-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With copper(l) iodide; trans-N1,N2-dimethylcyclohexane-1,2-diamine; potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 24h;Inert atmosphere;
N2 protection,3-methyl-1H-pyrazole-4-carboxylate(0.14 g, 1.0 mmol),CuI (19.1 mg, 0.1 mmol), K2CO3 (0.29 g, 2.1 mmol)III4 (0.32 g, 1.2 mmol),(E) -N, N'-dimethyl-1,2-cyclohexyl diamine (28.5 mg, 0.2 mmol) and DMF (3 mL) were added to a 25 mL two-necked flask and reacted at 110 C for 24 h,Cooled to room temperature, diluted with 10 mL of water, extracted with ethyl acetate (15 mL x 3)Saturated brine (10 mL), dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure,Silica gel column (V ethyl acetate: V petroleum ether = 4: 1),A yellow solid1- (3'-cyano-4'-morpholine-phenyl) -3-methyl-pyrazole-4-carboxylate (IV4)Yield 46.0%.
46%
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 24h;Inert atmosphere;
General procedure: Compound (11a-g or 12f-g) (1.2 mmol), CuI (19.1 mg, 0.1 mmol), trans-N,N'-dimethyl-1,2-cyclohexane-diamine (29 mg, 0.2 mmol), K2CO3 (0.29 g, 2.1 mmol) and DMF (3 mL) were added to a tube filled with argon. The mixture was stirred at 110 C for 24 h. The reaction was diluted with H2O (20 mL) and extracted with EtOAc (15 mL x 2). The combined organic phases were washed with H2O (20 mL x 2) and brine (30 mL), dried over MgSO4 and concentratedin a vacuum. The residue was purified by flash column chromatography (12-25% EtOAc in petroleum ether).
1-(3'-cyano-4'-piperidinophenyl)-3-methyl-pyrazole-4-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 24h;Inert atmosphere;
General procedure: Compound (11a-g or 12f-g) (1.2 mmol), CuI (19.1 mg, 0.1 mmol), trans-N,N'-dimethyl-1,2-cyclohexane-diamine (29 mg, 0.2 mmol), K2CO3 (0.29 g, 2.1 mmol) and DMF (3 mL) were added to a tube filled with argon. The mixture was stirred at 110 C for 24 h. The reaction was diluted with H2O (20 mL) and extracted with EtOAc (15 mL x 2). The combined organic phases were washed with H2O (20 mL x 2) and brine (30 mL), dried over MgSO4 and concentratedin a vacuum. The residue was purified by flash column chromatography (12-25% EtOAc in petroleum ether).
46.2%
With copper(l) iodide; trans-N1,N2-dimethylcyclohexane-1,2-diamine; potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 24h;Inert atmosphere;
N2 protection,Methyl-1H-pyrazole-4-carboxylate (0.14 g, 1.0 mmol), CuI (19.1 mg, 0.1 mmol), K2CO3 (0.29 g, 2.1 mmol)III1 (0.318 g, 1.2 mmol),(E) -N, N'-dimethyl-1,2-cyclohexyl diamine (28.5 mg, 0.2 mmol) and DMF (3 mL) were added to a 25 mL two-necked flask and reacted at 110 C for 24 h,Cooled to room temperature, diluted with 10 mL of water, extracted with ethyl acetate (15 mL x 3)Saturated brine (10 mL), dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure,Silica gel column (V ethyl acetate: V petroleum ether = 6: 1),0.15 g of methyl 4- (3'-cyano-4'-piperidine-phenyl) -3-methyl-pyrazole-4-carboxylate (IV1) as a yellow solid in a yield of 46.2%.
methyl 1-(4-isobutylphenyl)-3-methyl-1H-pyrazole-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With pyridine; copper diacetate; In N,N-dimethyl-formamide; at 25℃; for 14h;
A mixture of methyl 3-methyl- 1H-pyrazole-4-carboxylate (250.0 mg, 1.78 mmol), 4- isobutylphenyl boronic acid (412.9 mg, 2.32 mmol), pyridine (282.2 mg, 3.57 mmol) andcopper(II) acetate (486.0 mg, 2.68 mmol) in N,N-dimethylformamide (6 mL) was stirred at 25C for 14 h. The reaction was diluted with EtOAc (120 mL), washed with brine (50 mL x 3), dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (20% EtOAc in petroleum ether, Rf = 0.45) to give methyl 1-(4-isobutylphenyl)-3-methyl-1H-pyrazole-4- carboxylate (350 mg, 72% yield) as a white solid. LCMS (Method 5-95 AB, ESI): tR = 0.996mi [M+Hj = 272.9.
1-(3'-nitro-4'-morpholinophenyl)-3-methyl-pyrazole-4-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 24h;Inert atmosphere;
General procedure: Compound (11a-g or 12f-g) (1.2 mmol), CuI (19.1 mg, 0.1 mmol), trans-N,N'-dimethyl-1,2-cyclohexane-diamine (29 mg, 0.2 mmol), K2CO3 (0.29 g, 2.1 mmol) and DMF (3 mL) were added to a tube filled with argon. The mixture was stirred at 110 C for 24 h. The reaction was diluted with H2O (20 mL) and extracted with EtOAc (15 mL x 2). The combined organic phases were washed with H2O (20 mL x 2) and brine (30 mL), dried over MgSO4 and concentratedin a vacuum. The residue was purified by flash column chromatography (12-25% EtOAc in petroleum ether).
46.2%
With copper(l) iodide; trans-N1,N2-dimethylcyclohexane-1,2-diamine; potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 24h;Inert atmosphere;
N2 protection,Methyl-1H-pyrazole-4-carboxylate (0.14 g, 1.0 mmol), CuI (19.1 mg,(0.2 mmol), III5 (0.34 g, 1.2 mmol), (E) -N, N'-dimethyl-1,2-cyclohexylenediamine (28.5 mg, 0.2 mmol) And DMF (3 mL) were added to a 25 mL two-necked flask and reacted at 110 C for 24 h,Cooled to room temperature, diluted with 10 mL of water, extracted with ethyl acetate (15 mL x 3), washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure,Silica gel column (V ethyl acetate: V petroleum ether = 4: 1),(0.10 g) of methyl orange 1- (3'-nitro-4'-morpholine-phenyl) -3-methyl-pyrazole-4-carboxylate (IV5)Yield 46.2%.
methyl 1-(3'-cyano-4'-ethyloxy-phenyl)-3-methyl-pyrazol-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 24h;Inert atmosphere;
General procedure: Compound (3a-e) (1.2mmol), CuI (19.1mg, 0.1mmol), trans-N, N?-dimethyl-1, 2-cyclohexane-diamine (29mg, 0.2mmol), K2CO3 (0.29g, 2.1mmol) and DMF (3mL) were added to a tube filled with argon. The mixture was stirred at 110C for 24h, diluted with H2O (20mL), and extracted with EtOAc (15mL×2). The combined organic phases were washed with H2O (20mL×2) and brine (30mL), dried over MgSO4 and concentrated in a vacuum. The residue was purified by flash column chromatography (12-25% EtOAc in petroleum ether).
methyl 1-(3'-cyano-4'-isopropoxyphenyl)-3-methyl-pyrazol-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 24h;Inert atmosphere;
General procedure: Compound (3a-e) (1.2mmol), CuI (19.1mg, 0.1mmol), trans-N, N?-dimethyl-1, 2-cyclohexane-diamine (29mg, 0.2mmol), K2CO3 (0.29g, 2.1mmol) and DMF (3mL) were added to a tube filled with argon. The mixture was stirred at 110C for 24h, diluted with H2O (20mL), and extracted with EtOAc (15mL×2). The combined organic phases were washed with H2O (20mL×2) and brine (30mL), dried over MgSO4 and concentrated in a vacuum. The residue was purified by flash column chromatography (12-25% EtOAc in petroleum ether).
methyl 1-(3'-cyano-4'-isobutoxyphenyl)-3-methyl-pyrazol-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 24h;Inert atmosphere;
General procedure: Compound (3a-e) (1.2mmol), CuI (19.1mg, 0.1mmol), trans-N, N?-dimethyl-1, 2-cyclohexane-diamine (29mg, 0.2mmol), K2CO3 (0.29g, 2.1mmol) and DMF (3mL) were added to a tube filled with argon. The mixture was stirred at 110C for 24h, diluted with H2O (20mL), and extracted with EtOAc (15mL×2). The combined organic phases were washed with H2O (20mL×2) and brine (30mL), dried over MgSO4 and concentrated in a vacuum. The residue was purified by flash column chromatography (12-25% EtOAc in petroleum ether).
methyl 1-(3'-cyano-4'-neopentyloxyphenyl)-3-methylpyrazol-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 24h;Inert atmosphere;
General procedure: Compound (3a-e) (1.2mmol), CuI (19.1mg, 0.1mmol), trans-N, N?-dimethyl-1, 2-cyclohexane-diamine (29mg, 0.2mmol), K2CO3 (0.29g, 2.1mmol) and DMF (3mL) were added to a tube filled with argon. The mixture was stirred at 110C for 24h, diluted with H2O (20mL), and extracted with EtOAc (15mL×2). The combined organic phases were washed with H2O (20mL×2) and brine (30mL), dried over MgSO4 and concentrated in a vacuum. The residue was purified by flash column chromatography (12-25% EtOAc in petroleum ether).
methyl 1-(3'-cyano-4'-octyloxyphenyl)-3-methylpyrazol-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 24h;Inert atmosphere;
General procedure: Compound (3a-e) (1.2mmol), CuI (19.1mg, 0.1mmol), trans-N, N?-dimethyl-1, 2-cyclohexane-diamine (29mg, 0.2mmol), K2CO3 (0.29g, 2.1mmol) and DMF (3mL) were added to a tube filled with argon. The mixture was stirred at 110C for 24h, diluted with H2O (20mL), and extracted with EtOAc (15mL×2). The combined organic phases were washed with H2O (20mL×2) and brine (30mL), dried over MgSO4 and concentrated in a vacuum. The residue was purified by flash column chromatography (12-25% EtOAc in petroleum ether).