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Stage #1: With potassium permanganate In water; <i>tert</i>-butyl alcohol at 70℃; Stage #2: With hydrogenchloride In water; <i>tert</i>-butyl alcohol
S-Chloropyrazole-S-carboxylic acid (IV) A solution of KMnO4 (3.5 g, 22 mmol) in water (120 mL) was added in portions over a period of 5 h at 7O0C to a solution of 5-chloro-3-methylpyrazle (1.0 g, 8.8 mmol; see Intermediate (III) above) in water (50 mL) and fenr-butanol (1 mL). The mixture was stirred at 7O0C overnight and filtered through Celite.(R).. The colourless filtrate was concentrated and acidified with HCl (aq., 2M). Filtration gave the title compound as a white powder which was used without further purification. (Yield: 913 mg5 80percent). 1H-NMR (DMSO-d6): δ 6.80 (s, IH)5 4.40 (br s, IH).
67%
With potassium permanganate In water; <i>tert</i>-butyl alcohol at 70 - 75℃;
(b) S-Chloropyrazole-S-carboxylic acidA mixture of 5-chloro-3-methylpyrazole (3.6 mmol; see step (a) above), water (6 mL) and tert-bvttanol (1.2 mL) was heated to 750C5 after which KMnO4 (1.42 g, 9 mmol) was added. The mixture was stirred at 750C overnight and filtered hot. The solids were washed with boiling water. The combined cooled filtrates were extracted with EtOAc5 and the combined extracts washed with NaCl (sat., aq.), dried (MgSO4) and concentrated. The crude solid was recrystallised from EtOAc/hexane/pentane to give the sub-title compound as white crystals (Yield: 350 mg (67percent)). 1H-NMR (DMSO-d6, 400 MHz)5 δ 13.65 (br s, IH)5 6.80 (s, IH). (d) S-Chloropyrazole-S-carboxylic acidA solution of KMnO4 (3.5 g, 22 mmol) in water (120 mL) was added in portions over a period of 5 h at 7O0C to a solution of 5-chloro-3 -methylpyrazole (1.0 g, 8.8 mmol; see step (c) above) in water (50 mL) and tert-butanol (1 mL). The mixture was stirred at 7O0C overnight and filtered through Celite.(R).. The colourless filtrate was concentrated and acidified with HCl (aq., 2M). Filtration gave the title compound as a white powder which was used without further purification. (Yield: 913 mg, 80percent). 1H-NMR (DMSO-d6): δ 6.80 (s, IH), 4.40 (br s, IH).
67%
With potassium permanganate In water; <i>tert</i>-butyl alcohol at 75℃;
(b) S-Chloropyrazole-S-carboxylic acidA mixture of 5-chloro-3-methylpyrazole (3.6 mmol; see step (a) above), water (6 mL) and fert-butanol (1.2 mL) was heated to 750C, after which KMnO4 (1.42 g, 9 mmol) was added. The mixture was stirred at 75° C overnight and filtered hot. The solids were washed with boiling water. The combined cooled filtrates were extracted with EtOAc, and the combined extracts washed with NaCl (sat., aq.), dried (MgSO4) and concentrated. The crude solid was recrystallised from EPO <DP n="53"/>EtOAc/hexane/pentane to give the sub-title compound as white crystals (Yield:350 mg (67percent)).1H-NMR (DMSO-d6, 400 MHz), δ 13.65 (br s, IH), 6.80 (s, IH)
67%
With potassium permanganate; <i>tert</i>-butyl alcohol In water at 70 - 75℃;
A solution ofKMnC>4 (3.5 g, 22 mmol) in water (120 mL) was added in portions over aperiod of 5 h at 70 C to a solution of5-chloro-3-methylpyrazole (1.0 g, 8.8 mmol; see step (c) above) in water (50 mL) and fc/^-butanol (1 mL). The mixture was stirred at 70 C overnight and filtered through Celite.(R).. The colourless filtrate was concentrated and acidified with HC1 (2M). Filtration gave the title compound as a white powder which was used without further purification. (Yield: 913 mg, 80percent). ^-NMR (DMSO-dg): 5 13.65 (br s, 1H), 6.80 (s, 1H), 4.40 (bs, 1H).; A mixture of5-chloro-3-methylpyrazole (3.6 mmol; see step (a) above), water (6 mL), /e/Y-butanol (1.2 mL) and KMn04 (1.42 g, 9 mmol) was stirred at 75 C overnight. The hot mixture was filtered and the solids washed with boiling water. The combined filtrates were extracted twice with EtOAc. The combined extracts were washed with Nad (aq, sat), dried (MgS04) and concentrated to provide a solid, which was crystallised from EtOAc/hexane/pentane to give the sub-title product as white crystals (Yield: 350 mg (67percent)). 'H-NMR (DMSO-dg, 400 MHz), 5 13.65 (br s, 1H), 6.80 (s, 1H), 4.40 (bs, 1H).
67%
With potassium permanganate In water; <i>tert</i>-butyl alcohol at 70 - 75℃;
(b) 5-Chloropyrazole-3-carboxylic acid..A mixture of 5-chloro-3-methylpyrazole (3.6 mmol; see step (a) above), water (6 mL) and terf-butanol (1.2 mL) was heated to 750C, after which KMnO4 (1.42 g, 9 mmol) was added. The mixture was stirred at 75°C overnight and filtered hot. The solids were washed with boiling water. The combined cooled filtrates were extracted with EtOAc, and the combined extracts washed with NaCI (sat., aq.), dried (MgSO4) and concentrated. The crude solid was recrystallised from EtOAc/hexane/pentane to give the sub-title compound as white crystals (Yield: 350 mg (67percent)). 1H-NMR (DMSO-d6, 400 MHz), δ 13.65 (br s, 1 H), 6.80 (s, 1 H). (d) 5-Chloropyrazole-3-carboxylic acid. A solution of KMnO4 (3.5 g, 22 mmol) in water (120 mL) was added in portions over a period of 5 h at 700C to a solution of 5-chloro-3-methylpyrazole (1.0 g, 8.8 mmol; see step (c) above) in water (50 mL) and terf-butanol (1 mL). The mixture was stirred at 7O0C overnight and filtered through Celite.(R).. The colourless filtrate was concentrated and acidified with HCI (aq., 2M). Filtration gave the title compound as a white powder which was used without further purification. (Yield: 913 mg, 80percent). 1H-NMR (DMSO-d6): δ 6.80 (s, 1 H), 4.40 (br s, 1 H).
S-Chloropyrazole-S-carboxylic acid (IV) A solution of KMnO4 (3.5 g, 22 mmol) in water (120 mL) was added in portions over a period of 5 h at 7O0C to a solution of 5-chloro-3-methylpyrazle (1.0 g, 8.8 mmol; see Intermediate (III) above) in water (50 mL) and fenr-butanol (1 mL). The mixture was stirred at 7O0C overnight and filtered through Celite. The colourless filtrate was concentrated and acidified with HCl (aq., 2M). Filtration gave the title compound as a white powder which was used without further purification. (Yield: 913 mg5 80%). 1H-NMR (DMSO-d6): delta 6.80 (s, IH)5 4.40 (br s, IH).
67 - 80%
With potassium permanganate; In water; tert-butyl alcohol; at 70 - 75℃;Product distribution / selectivity;
(b) S-Chloropyrazole-S-carboxylic acidA mixture of <strong>[15953-45-4]5-chloro-3-methylpyrazole</strong> (3.6 mmol; see step (a) above), water (6 mL) and tert-bvttanol (1.2 mL) was heated to 750C5 after which KMnO4 (1.42 g, 9 mmol) was added. The mixture was stirred at 750C overnight and filtered hot. The solids were washed with boiling water. The combined cooled filtrates were extracted with EtOAc5 and the combined extracts washed with NaCl (sat., aq.), dried (MgSO4) and concentrated. The crude solid was recrystallised from EtOAc/hexane/pentane to give the sub-title compound as white crystals (Yield: 350 mg (67%)). 1H-NMR (DMSO-d6, 400 MHz)5 delta 13.65 (br s, IH)5 6.80 (s, IH). (d) S-Chloropyrazole-S-carboxylic acidA solution of KMnO4 (3.5 g, 22 mmol) in water (120 mL) was added in portions over a period of 5 h at 7O0C to a solution of 5-chloro-3 -methylpyrazole (1.0 g, 8.8 mmol; see step (c) above) in water (50 mL) and tert-butanol (1 mL). The mixture was stirred at 7O0C overnight and filtered through Celite. The colourless filtrate was concentrated and acidified with HCl (aq., 2M). Filtration gave the title compound as a white powder which was used without further purification. (Yield: 913 mg, 80%). 1H-NMR (DMSO-d6): delta 6.80 (s, IH), 4.40 (br s, IH).
67%
With potassium permanganate; In water; tert-butyl alcohol; at 75℃;Product distribution / selectivity;
(b) S-Chloropyrazole-S-carboxylic acidA mixture of <strong>[15953-45-4]5-chloro-3-methylpyrazole</strong> (3.6 mmol; see step (a) above), water (6 mL) and fert-butanol (1.2 mL) was heated to 750C, after which KMnO4 (1.42 g, 9 mmol) was added. The mixture was stirred at 75 C overnight and filtered hot. The solids were washed with boiling water. The combined cooled filtrates were extracted with EtOAc, and the combined extracts washed with NaCl (sat., aq.), dried (MgSO4) and concentrated. The crude solid was recrystallised from EPO <DP n="53"/>EtOAc/hexane/pentane to give the sub-title compound as white crystals (Yield:350 mg (67%)).1H-NMR (DMSO-d6, 400 MHz), delta 13.65 (br s, IH), 6.80 (s, IH)
67 - 80%
With potassium permanganate; tert-butyl alcohol; In water; at 70 - 75℃;
A solution ofKMnC>4 (3.5 g, 22 mmol) in water (120 mL) was added in portions over aperiod of 5 h at 70 C to a solution of<strong>[15953-45-4]5-chloro-3-methylpyrazole</strong> (1.0 g, 8.8 mmol; see step (c) above) in water (50 mL) and fc/^-butanol (1 mL). The mixture was stirred at 70 C overnight and filtered through Celite. The colourless filtrate was concentrated and acidified with HC1 (2M). Filtration gave the title compound as a white powder which was used without further purification. (Yield: 913 mg, 80%). ^-NMR (DMSO-dg): 5 13.65 (br s, 1H), 6.80 (s, 1H), 4.40 (bs, 1H).; A mixture of<strong>[15953-45-4]5-chloro-3-methylpyrazole</strong> (3.6 mmol; see step (a) above), water (6 mL), /e/Y-butanol (1.2 mL) and KMn04 (1.42 g, 9 mmol) was stirred at 75 C overnight. The hot mixture was filtered and the solids washed with boiling water. The combined filtrates were extracted twice with EtOAc. The combined extracts were washed with Nad (aq, sat), dried (MgS04) and concentrated to provide a solid, which was crystallised from EtOAc/hexane/pentane to give the sub-title product as white crystals (Yield: 350 mg (67%)). 'H-NMR (DMSO-dg, 400 MHz), 5 13.65 (br s, 1H), 6.80 (s, 1H), 4.40 (bs, 1H).
67 - 80%
With potassium permanganate; In water; tert-butyl alcohol; at 70 - 75℃;Product distribution / selectivity;
(b) 5-Chloropyrazole-3-carboxylic acid..A mixture of <strong>[15953-45-4]5-chloro-3-methylpyrazole</strong> (3.6 mmol; see step (a) above), water (6 mL) and terf-butanol (1.2 mL) was heated to 750C, after which KMnO4 (1.42 g, 9 mmol) was added. The mixture was stirred at 75C overnight and filtered hot. The solids were washed with boiling water. The combined cooled filtrates were extracted with EtOAc, and the combined extracts washed with NaCI (sat., aq.), dried (MgSO4) and concentrated. The crude solid was recrystallised from EtOAc/hexane/pentane to give the sub-title compound as white crystals (Yield: 350 mg (67%)). 1H-NMR (DMSO-d6, 400 MHz), delta 13.65 (br s, 1 H), 6.80 (s, 1 H). (d) 5-Chloropyrazole-3-carboxylic acid. A solution of KMnO4 (3.5 g, 22 mmol) in water (120 mL) was added in portions over a period of 5 h at 700C to a solution of <strong>[15953-45-4]5-chloro-3-methylpyrazole</strong> (1.0 g, 8.8 mmol; see step (c) above) in water (50 mL) and terf-butanol (1 mL). The mixture was stirred at 7O0C overnight and filtered through Celite. The colourless filtrate was concentrated and acidified with HCI (aq., 2M). Filtration gave the title compound as a white powder which was used without further purification. (Yield: 913 mg, 80%). 1H-NMR (DMSO-d6): delta 6.80 (s, 1 H), 4.40 (br s, 1 H).
5-chloro-N-(5-chloropyridin-2-yl)pyrazole-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 3h;
Example 2S-Chloro-lambda^CS-chloropyridm^-yDpyrazole-S-carboxamide TBTU (1.2 mmol) was added to a solution of intermediate (II) (1.5 mmol), 2-amino-5-chloropyridine (1.8 mmol) and DIPEA (2.0 mmol) in dry DMF (2 mL). The mixture was stirred at 6O0C for 3 h and concentrated. Water was added and the mixture was extracted with EtOAc. The combined extracts were washed with <n="64"/>CaCl2 (sat., aq.), dried (Na2SO4) and concentrated. Crystallisation from EtOAc gave the title compound as a white powder (Yield: 170 mg (44%)).1H-NMR (DMSO-J6): delta 14.06 (br s5 IH), 11.13 (br s, IH)5 8.55 (d, IH), 8.19 (d,IH), 7.98 (dd, IH), 7.32 (s, IH).
4,5-Dichloropyrazole-3-carboxylic acid (VIII) Chlorine gas was bubbled slowly through a stirred solution of 5-chloropyrazole-3- carboxylic acid (3.00 g, 20.5 mmol; see intermediate (IV) above) in water (2.0 L) at rt over 3 h. The solution was stirred for 18 h in an open flask and then concentrated in vacuo. The resulting slurry was extracted with EtOAc (3x100 mL)5 the combined organic phases were washed with NaCl (sat., aq., 100 roL), dried (Na2SO4) and concentrated in vacuo to give the product as a white powder (Yield 3.2O g5 86 %). MS OT-H) OT^Z 179. 1HNMR (DMSO-J6, 400 MHz) delta 14.44 (s, IH)5 14.09 (s, IH).
86%
With chlorine; In water; at 20℃; for 21h;
4,5-Dichloropyrazole-3-carboxyh'c acid (TV")Chlorine gas was bubbled slowly through a stirred solution of 5-chloropyrazole-3- carboxylic acid (Intermediate II, 3.00 g, 20.5 mmol) in water (2.0 L) at rt over 3 h. The solution was stirred for 18 h in an open flask and then concentrated in vacuo. The slurry was extracted with ethyl acetate (3x100 mL), the combined extracts were washed with NaCl (sat., aq.; 100 mL) and dried (Na2SO4). The solvent was removed in vacuo to give the product as a white powder. Yield 3.20 g (86 %). MS (MT-H) Wk= 179. 1H NMR (DMSO^6, 400 MHz) delta 14.44 (s, IH), 14.09 (s, IH). 13CNMR (CD3OD, 100 MHz) delta 160.0; 139.6; 133.1; 112.4.
86%
With chlorine; In water; at 20℃; for 21h;
4,5-Dichloropyrazole-3-carboxylic acid (II)Chlorine gas was bubbled slowly through a stirred solution of 5-chloropyrazole-3- carboxylic acid (Intermediate I, 3.00 g, 20.5 mmol) in water (2.0 L) at room temperature over 3 h. The solution was stirred for 18 h in an open flask and then concentrated in vacuo. The slurry was extracted with ethyl acetate (3x100 mL), the combined extracts were washed with NaCI (sat., aq.; 100 mL) and dried (Na2SO4). The solvent was removed in vacuo to give the product as a white powder. Yield 3.20 g (86 %). MS (M--H) m/z = 179. 1H NMR (DMSOd6, 400 MHz) delta 14.44 (s, 1 H), 14.09 (s, 1 H). 13C NMR (CD3OD, 100 MHz) delta 160.0; 139.6; 133.1 ; 1 12.4.
(c) 5-Chloro-iV-('2-chloro-4-fluorophenyl)pyrazole-3-carboxamideA mixture of S-chloropyrazole-S-carboxylic acid (1 mmol; see step (b) above) and SOCl2 (1 mL) was heated at reflux for 18 h, cooled and concentrated. A portion of the resulting white solid (70 mg) was mixed with DMAP (0.27 mmol) and 2-chloro-4-fluoroaniline (0.27 mmol) in CH2Cl2 (10 mL) and stirred at 6O0C for 2O h. After cooling to rt, the solid was filtered off and washed with CH2Cl2. The solid was dissolved in EtOAc (15 mL) and washed with HCl (aq., IM) and NaCl (sat., aq.). The organic phase was dried (MgSO4) and concentrated. Crystallisation (EtOH/water) furnished the title compound as a white powder (Yield: 28.9 mg (39%)). MS (M++H) tau»/z = 274.1H-NMR(DMSO^6, 400 MHz), delta 10.21 (br s, IH), 7.58 (dd, 2H)5 7.27-7.32 (m, IH), 7.09 (br s, IH).
2.7"Dichlorodirhoyrazolori,5-a:r,5'-dlpyrazme-4,9-dione (IH) A mixture of S-chloropyrazole-S-carboxylic acid (80 mg; see step (b) above) and SOCl2 (1 mL) was heated at 8O0C for 18 L The excess SOCl2 was removed in vacuo and the crude product (69 mg) was used without purification.
5-chloro-N-(5,6-dimethylpyridin-2-yl)pyrazole-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With dmap; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 72h;
Method E A mixture of TBTU (642 mg, 2.0 mmol), pyrazole-3-carboxylic acid or 5-chloro pyrazole-3-carboxylic acid (intermediate II) (1.0 mmol), the relevant arylamine (1.0 mmol), DIPEA (348 muL, 2.0 mmol) and DMAP (12 mg, 0.1 mmol) in dry DMF (5 mL) was stirred at 80 0C for 3 days. After cooling to rt the mixture was concentrated and hydrochloric acid (IM, 10 mL) was added. The mixture was extracted with EtOAc (4 x 10 mL) , the combined organic phases washed with NaCl (sat., aq.; 20 mL), dried (Na2SO4), concentrated and purified by chromatography (EtO Ac/heptane) to give the desired compound.
5-chloro-N-(2-difluoromethoxyphenyl)pyrazole-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
With dmap; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 72h;
Method C A mixture of TBTU (642 mg, 2.0 mmol), the relevant substituted pyrazole-3- carboxylic acid (intermediate FV, 1.0 mmol), the relevant arylamine (1.0 mmol), DIPEA (348 muL, 2.0 mmol) and DMAP (12 mg, 0.1 mmol) in dry DMF (5 mL) was stirred at 80 0C for 3 days. After cooling to rt the mixture was concentrated and the residue acidified with HCl (aq., IM; 10 mL). The mixture was extracted with EtOAc (4x10 mL), the combined organic phases were then washed with NaCl (sat., aq.; 20 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (EtO Ac/heptane).
(S)-3-amino-N-(4-cyano-3-trifluoromethylphenyl)-2-hydroxy-2-methylpropanamide[ No CAS ]
(S)-5-chloro-N-(3-((4-cyano-3-trifluoromethylphenyl)amino)-2-hydroxy-2-methyl-3-oxopropyl)-1H-pyrazole-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
Add in 100mL round bottom flask<strong>[881668-70-8]5-chloro-1H-pyrazole-3-carboxylic acid</strong> (0.122 g, 0.8355 mmol),1.5 mL of anhydrous DMF as a solvent, Add EDCI (0.16 g, 1.0444 mmol), DIPEA (0.24 mL, 1.3926 mmol) and HOBT (32 mg, 0.2089 mmol), Stir for 20 minutes. Add another starting material (S)-3-amino-N-(4-cyano-3-trifluoromethyl-phenyl)-2-hydroxy-2-methylpropanamide (0.20 g, 0.6963 mmol) a solution of 4.0 mL of anhydrous DMF, Then the reaction solution is under argon protection. Stir at room temperature for 3 days. After confirming the completion of the reaction by thin layer chromatography, ethyl acetate and water were added, the two phases were separated, and the organic phase was drained to obtain Oily substance. Separation by silica gel column chromatography (mobile phase: methylene chloride:methanol = 9:1), purified to give pale yellow powder 0.15 g, the yield was about 51.0%.
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