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Chemistry
Organic Building Blocks
Pyrazoles
nitro-pyrazole-carboxylate
Methyl 4-nitro-1H-pyrazole-3-carboxylate
Chemistry
Organic Building Blocks
Heterocyclic Building Blocks
Pyrazoles
Esters Nitroes
nitro-pyrazole-carboxylate

[ CAS No. 138786-86-4 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
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Product Details of [ 138786-86-4 ]

CAS No. :138786-86-4 MDL No. :MFCD00505604
Formula : C5H5N3O4 Boiling Point : -
Linear Structure Formula :- InChI Key :ARAFBUCGMOKZMI-UHFFFAOYSA-N
M.W : 171.11 Pubchem ID :1276704
Synonyms :

Calculated chemistry of [ 138786-86-4 ]

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.2
Num. rotatable bonds : 3
Num. H-bond acceptors : 5.0
Num. H-bond donors : 1.0
Molar Refractivity : 38.69
TPSA : 100.8 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.18 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.37
Log Po/w (XLOGP3) : 0.23
Log Po/w (WLOGP) : 0.1
Log Po/w (MLOGP) : -1.37
Log Po/w (SILICOS-IT) : -1.23
Consensus Log Po/w : -0.38

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.16
Solubility : 11.9 mg/ml ; 0.0698 mol/l
Class : Very soluble
Log S (Ali) : -1.91
Solubility : 2.12 mg/ml ; 0.0124 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.69
Solubility : 35.1 mg/ml ; 0.205 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.17

Safety of [ 138786-86-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 138786-86-4 ]

* 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.

  • Upstream synthesis route of [ 138786-86-4 ]
  • Downstream synthetic route of [ 138786-86-4 ]

[ 138786-86-4 ] Synthesis Path-Upstream   1~18

  • 1
  • [ 138786-86-4 ]
  • [ 360056-45-7 ]
YieldReaction ConditionsOperation in experiment
99% With palladium 10% on activated carbon In methanol at 20℃; for 16 h; Reference Example 2
Methyl 4-amino-1H-pyrazole-3-carboxylate
A mixture of methyl 4-nitro-1H-pyrazole-3-carboxylate obtained in Reference Example 1 (9.63 g, 56.3 mmol), 10percent palladium/carbon (1.00 g) and methanol (150 mL) was stirred under hydrogen atmosphere at room temperature for 16 hr.
The catalyst was filtrated, and the solvent was evaporated under reduced pressure to give the title compound (7.87 g, yield 99percent).
1H-NMR (CDCl3): δ 3.93 (3H, s), 4.08 (2H, brs), 7.25 (1H, s).
99% With hydrogen In methanol at 20℃; for 16 h; A mixture of methyl 4-nitro-1H-pyrazole-3-carboxylate obtained in Reference Example 1 (9.63 g, 56.3 mmol), 10percent palladium/carbon (1.00 g) and methanol (150 mL) was stirred under hydrogen atmosphere at room temperature for 16 hr. The catalyst was filtrated, and the solvent was evaporated under reduced pressure to give the title compound (7.87 g, yield 99percent). 1H-NMR (CDCl3):δ 3.93(3H, s), 4.08(2H, brs), 7.25(1H, s).
98.9% With hydrogen In ethanol at 28 - 30℃; for 5 - 10 h; A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with palladium on carbon (10percent wet paste, 0.170Kg, 0.14wt) under nitrogen. In a separate vessel, a slurry of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (1.210Kg, 7.07mol, lwt) in ethanol (12.10L, lOvol) was warmed to 30 to 350C to effect dissolution and the solution added to the catalyst under nitrogen. Following a nitrogen-hydrogen purge sequence an atmosphere of hydrogen was introduced and the reaction mixture maintained at 28 to 3O0C until reaction completion (5 to 10 hours) was noted by 1H NMR analysis (d6-DMSO). Following a purge cycle, the reaction mixture under nitrogen was filtered and the liquors concentrated under reduced pressure to give 4-amino-lH-pyrazole-3-carboxylic acid methyl ester (0.987Kg5 98.9percentth).; A suspension of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (1.084Kg, 6.33mol, l.Owt) and ethanol (10.84L, lO.Ovol) was heated to and maintained at 30 to 35°C until complete dissolution occurred. 10percent Palladium on carbon (10percent Pd/C wet paste, 0.152Kg, 0.14wt) was charged to a separate flask under nitrogen and a vacuum / nitrogen purge cycle was performed three times. The solution of 4-nitro- lH-pyrazole-3-carboxylic acid methyl ester in ethanol was charged to the catalyst and a vacuum / nitrogen purge cycle was performed three times. A vacuum / hydrogen purge cycle was performed three times and the reaction was placed under an atmosphere of hydrogen. The reaction mixture was stirred at 28 to 30°C until deemed complete by 1H NMR analysis (d6-DMSO). The mixture was filtered under nitrogen and concentrated under vacuum at 35 to 450C to give 4-amino-lH- pyrazole-3-carboxylic acid methyl ester (0.883Kg, 98.9percent) as a purple solid.
98.9% With hydrogen In ethanol at 28 - 30℃; for 5 - 20 h; Stage 2: Preparation of 4-amino-l/7-pyrazole-3-carboxylic acid methyl esterA 20 L reaction vessel equipped with a digital thermometer and stirrer was charged with palladium on carbon (10percent wet paste, 0.170 Kg, 0.14 wt) under nitrogen. In a separate vessel a slurry of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester(1.210 Kg, 7.07 mol, 1 wt) in ethanol (12.10 L, 10 vol) was warmed to 30 to 35 0C to effect dissolution and the solution added to the catalyst under nitrogen. Following a nitrogen-hydrogen purge sequence an atmosphere of hydrogen was introduced and the reaction mixture maintained at 28 to 30 0C until reaction completion (5 to 10 hours) was noted by 1H NMR analysis (d6 -DMSO). Following a purge cycle, the reaction mixture under nitrogen was filtered and the liquors concentrated under reduced pressure to give 4-amino-li/-pyrazole-3-carboxylic acid methyl ester (0.987 Kg, 98.9percent).; HB. Synthesis of 4-amino-lH-pyrazole-3-carboxylic acid methyl esterA mixture of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (34.6 mmol) and 10percent Pd/C (650 mg) in EtOH (150 ml) is stirred under an atmosphere of hydrogen for 20 hours. The mixture is filtered through a plug of Celite, reduced in vacuo and dried through azeotrope with toluene to afford 4-amino-lH-pyrazole-3-carboxylic acid methyl ester
98.9% With hydrogen In ethanol at 28 - 35℃; for 5 - 10 h; A 20 L reaction vessel equipped with a digital thermometer and stirrer was charged with palladium on carbon (10percent wet paste, 0.170 Kg, 0.14 wt) under nitrogen. In a separate vessel a slurry of 4-nitro-1H-pyrazole-3- carboxylic acid methyl ester (1.210 Kg, 7.07 mol, 1 wt) in ethanol (12.10 L, 10 vol) was warmed to 30 to 35 °C to effect dissolution and the solution added to the catalyst under nitrogen. Following a nitrogen-hydrogen purge sequence an atmosphere of hydrogen was introduced and the reaction mixture maintained at 28 to 30 °C until reaction completion (5 to 10 hours) was noted by 1H NMR analysis (dβ-DMSO). Following a purge cycle, the reaction mixture under nitrogen was filtered and the liquors concentrated under reduced pressure to give 4- amino-1H-pyrazole-3-carboxylic acid methyl ester (0.987 Kg, 98.9percent).
98.9% With hydrogen In ethanol at 28 - 35℃; for 5 - 10 h; A 20 L reaction vessel equipped with a digital thermometer and stirrer was charged with palladium on carbon (10percent wet paste, 0.170 Kg, 0.14 wt) under nitrogen. In a separate vessel a slurry of 4-nitro-1H-pyrazole-3- carboxylic acid methyl ester (1.210 Kg, 7.07 mol, 1 wt) in ethanol (12.10 L, 10 vol) was warmed to 30 to 35 °C to effect dissolution and the solution added to the catalyst under nitrogen. Following a nitrogen-hydrogen purge sequence an atmosphere of hydrogen was introduced and the reaction mixture maintained at 28 to 30 °C until reaction completion (5 to 10 hours) was noted by 1H NMR analysis (dβ-DMSO). Following a purge cycle, the reaction mixture under nitrogen was filtered and the liquors concentrated under reduced pressure to give 4- amino-1H-pyrazole-3-carboxylic acid methyl ester (0.987 Kg, 98.9percent).
98.9% With hydrogen In ethannol at 28 - 30℃; for 5 - 10 h; A 20 L reaction vessel equipped with a digital thermometer and stirrer was charged with palladium on carbon (10percent wet paste, 0.170 Kg, 0.14 wt) under nitrogen. In a separate vessel a slurry of 4-nitro-1 H-pyrazole-3-carboxylic acid methyl ester (1.210 Kg, 7.07 mol, 1 wt) in ethanol (12.10 L, 10 vol) was warmed to 30 to 35 0C to effect dissolution and the solution added to the catalyst under nitrogen. Following a nitrogen-hydrogen purge sequence an atmosphere of hydrogen was introduced and the reaction mixture maintained at 28 to 30 0C until reaction completion (5 to 10 hours) was noted by 1H NMR analysis (d6- DMSO). Following a purge cycle, the reaction mixture under nitrogen was filtered and the liquors concentrated under reduced pressure to give 4-amino-1/-/-pyrazole-3-carboxylic acid methyl ester (0.987 Kg, 98.9percent).
98.9% With hydrogen In ethanol at 28 - 35℃; for 5 - 10 h; Stage 5: Synthesis of 4-amino-lη-ρyrazole-3-carboxylic acid methyl ester; A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with palladium on carbon (10percent wet paste, 0.170Kg, 0.14wt) under nitrogen. In a separate vessel, a slurry of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (1.210Kg, 7.07mol, lwt) in ethanol (12.1OL, lOvol) was warmed to 30 to 350C to effect dissolution and the solution added to the catalyst under nitrogen. Following a nitrogen-hydrogen purge sequence an atmosphere of hydrogen was introduced and the reaction mixture maintained at 28 to 300C until reaction completion (5 to 10 hours) was noted by 1H NMR analysis (dβ-DMSO). Following a purge cycle, the reaction mixture under nitrogen was filtered and the liquors concentrated under reduced pressure to give 4-amino-lH-pyrazole-3-carboxylic acid methyl ester (0.987Kg, 98.9percentth).; Stage 5: Preparation of 4-amino-lH-pyrazole-3-carboxylic acid methyl ester.; C5H5N3O4 C5H7N3O2FW: 171.11 FW: 141.13A suspension of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (1.084Kg, 6.33mol, l.Owt) and ethanol (10.84L, lO.Ovol) was heated to and maintained at 30 to 35°C until complete dissolution occurred. 10percent Palladium on carbon (10percent Pd/C wet paste, 0.152Kg, 0.14wt) was charged to a separate flask under nitrogen and a vacuum / nitrogen purge cycle was performed three times. The solution of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester in ethanol was charged to the catalyst and a vacuum / nitrogen purge cycle was performed three times. A vacuum / hydrogen purge cycle was performed three times and the reaction was placed under an atmosphere of hydrogen. The reaction mixture was stirred at 28 to 300C until deemed <n="245"/>complete by 1H NMR analysis (d6-DMSO). The mixture was filtered under nitrogen and concentrated under vacuum at 35 to 450C to give 4-amino-lH-pyrazole-3-carboxylic acid methyl ester (0.883Kg, 98.9percent) as a purple solid.
98.9% at 28 - 35℃; for 5 - 20 h; A 20 L reaction vessel equipped with a digital thermometer and stirrer was charged with palladium on carbon (10percent wet paste, 0.170 Kg, 0.14 wt) under nitrogen. In a separate vessel a slurry of 4-nitro-1 H-pyrazole-3-carboxylic acid methyl ester (1.210 Kg, 7.07 mol, 1 wt) in ethanol (12.10 L, 10 vol) was warmed to 30 to 35 0C to effect dissolution and the solution added to the catalyst under nitrogen. Following a nitrogen-hydrogen purge sequence an atmosphere of hydrogen was introduced and the reaction mixture maintained at 28 to 30 0C until reaction completion (5 to 10 hours) was noted by 1H NMR analysis (d6- DMSO). Following a purge cycle, the reaction mixture under nitrogen was filtered and the liquors concentrated under reduced pressure to give 4-amino-1/-/-pyrazole-3-carboxylic acid methyl ester (0.987 Kg, 98.9percent).; A mixture of 4-nitro-1 H-pyrazole-3-carboxylic acid methyl ester and 10percent Pd/C in EtOH was stirred under an atmosphere of hydrogen for 20 hours. The mixture was filtered through a plug of Celite, reduced in vacuo and dried through azeotrope with toluene to afford 4-amino-1 H-pyrazole-3-carboxylic acid methyl ester.Stage 2: Preparation of 4-amino-1 H-pvrazole-3-carboxvlic acid methyl esterA suspension of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.467Kg, 8.57 MoI, 1.0 wt) and ethanol (14.70L, 10.0 vol) was heated to and maintained at 30 to 350C until complete dissolution occurred. 10percent Palladium on carbon (10percent Pd/C wet paste, 0.205Kg, 0.14 wt) was charged to a separate flask under nitrogen and a vacuum / nitrogen purge <n="108"/>cycle performed (x3). The solution of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester in ethanol was charged to the catalyst and the vacuum / nitrogen purge cycle repeated (x3). A vacuum / hydrogen purge cycle was performed (x3) and the reaction placed under an atmosphere of hydrogen. The reaction mixture was stirred at 28 to 300C until deemed complete by 1H NMR analysis (de-DMSO). The mixture was filtered under nitrogen and concentrated under vacuum at 35 to 45°C to give 4-amino-1 H-pyrazole-3-carboxylic acid methyl ester [, 1.184Kg, 97.9percentth, 80.7percentw/w, 1H NMR (d6-DMSO) concordant with structure, corrected for 0.27percentw/w entrained ethanol] as an off-white solid.
97.9% With hydrogen In ethanol at 28 - 30℃; for 5 - 20 h; A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with palladium on carbon (10percent wet paste, 0.170Kg, 0.14wt) under nitrogen. In a separate vessel, a slurry of 4-nitro-1/-/-pyrazole-3-carboxylic acid methyl ester (1.210Kg, 7.07mol, 1wt) in ethanol (12.10L, 10vol) was warmed to 30 to 350C to effect dissolution and the <n="293"/>solution added to the catalyst under nitrogen. Following a nitrogen-hydrogen purge sequence an atmosphere of hydrogen was introduced and the reaction mixture maintained at 28 to 3O0C until reaction completion (5 to 10 hours) was noted by 1H NMR analysis (d6- DMSO). Following a purge cycle, the reaction mixture under nitrogen was filtered and the liquors concentrated under reduced pressure to give 4-amino-1 H-pyrazole-3-carboxylic acid methyl ester (0.987Kg, 98.9percentth).A suspension of 4-nitro-1 H-pyrazole-3-carboxylic acid methyl ester (1.084Kg, 6.33mol, 1.0wt) and ethanol (10.84L, 10.0vol) was heated to and maintained at 30 to 350C until complete dissolution occurred. 10percent Palladium on carbon (10percent Pd/C wet paste, 0.152Kg, 0.14wt) was charged to a separate flask under nitrogen and a vacuum / nitrogen purge cycle was performed three times. The solution of 4-nitro-1 H-pyrazole-3-carboxylic acid methyl ester in ethanol was charged to the catalyst and a vacuum / nitrogen purge cycle was performed three times. A vacuum / hydrogen purge cycle was performed three times and the reaction was placed under an atmosphere of hydrogen. The reaction mixture was stirred at 28 to 300C until deemed complete by 1H NMR analysis (d6-DMSO). The mixture was filtered under nitrogen and concentrated under vacuum at 35 to 45°C to give 4-amino- 1 H-pyrazole-3-carboxylic acid methyl ester (0.883Kg, 98.9percent) as a purple solid. A mixture of 4-nitro-1 H-pyrazole-3-carboxylic acid methyl ester and 10percent Pd/C in EtOH was stirred under an atmosphere of hydrogen for 20 hours. The mixture was filtered through a plug of Celite, reduced in vacuo and dried through azeotrope with toluene to afford 4-amino-1 H-pyrazole-3-carboxylic acid methyl ester.1H NMR (400 MHz, MeOD) δ 7.2 (s, 1 H), 3.9 (s, 3H) A suspension of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.467Kg, 8.57 MoI, 1.0 wt) and ethanol (14.70L, 10.0 vol) was heated to and maintained at 30 to 35°C until complete dissolution occurred. 10percent Palladium on carbon (10percent Pd/C wet paste, 0.205Kg, 0.14 wt) was charged to a separate flask under nitrogen and a vacuum / nitrogen purge <n="364"/>cycle performed (x3). The solution of 4-nitro-1H-pyrazoIe-3-carboxylic acid methyl ester in ethanol was charged to the catalyst and the vacuum / nitrogen purge cycle repeated (x3). A vacuum / hydrogen purge cycle was performed (x3) and the reaction placed under an atmosphere of hydrogen. The reaction mixture was stirred at 28 to 300C until deemed complete by 1H NMR analysis (d6-DMSO). The mixture was filtered under nitrogen and concentrated under vacuum at 35 to 450C to give 4-amino-1 H-pyrazole-3-carboxylic acid methyl ester [1.184Kg, 97.9percentth, 80.7percentw/w, 1H NMR (d6-DMSO) concordant with structure, corrected for 0.27percentw/w entrained ethanol] as an off-white solid.
97.9% With hydrogen In ethanol at 28 - 35℃; Industry scale Stage 2: Preparation of 4-ammo-lH-pyrazole-3-carboxyric acid methyl esterC5H5N3O4 C5H7N3O2 FW: 171.11 FW: 141.13A suspension of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (1.467Kg, 8.57 MoI, 1.0 wt) and ethanol (14.7OL, 10.0 vol) was heated to and maintained at 30 to 350C until complete dissolution occurred. 10percent Palladium on carbon (10percent Pd/C wet paste, 0.205Kg, 0.14 wt) was charged to a separate flask under nitrogen and a vacuum / nitrogen purge cycle performed (x3). The solution of 4-nitro-lH- pyrazole-3-carboxylic acid methyl ester in ethanol was charged to the catalyst and the vacuum / nitrogen purge cycle repeated (x3). A vacuum / hydrogen purge cycle was performed (x3) and the reaction placed under an atmosphere of hydrogen. The reaction mixture was stirred at 28 to 3O0C until deemed complete by H NMR analysis (d6-DMSO). The mixture was filtered under nitrogen and concentrated under vacuum at 35 to 45°C to give 4-amino-lH-pyrazole-3-carboxylic acid methyl ester [1.184Kg, 97.9percentth, 80.7percentw/w, 1H NMR (d6-DMSO) concordant with structure, corrected for 0.27percentw/w entrained ethanol] as an off-white solid.
95% With ammonium formate In methanol at 20℃; for 17 h; REFERENCE EXAMPLE 7; 4-Amino-1H-pyrazole-3-carboxylic acid methyl ester; To a solution of 4-nitro-1/-/-pyrazole-3-carboxylic acid methyl ester (1.3 g, 7.6 mmol) in MeOH (100 ml) were added ammonium formate (3.35 g, 53.2 mmol) and 5percent palladium on carbon (225 mg). The reaction was stirred for 17 h at room temperature under a nitrogen atmosphere. Removal of the catalyst by filtration, followed by evaporation of the solvent afforded the crude title compound as a brown solid (yield: 95percent).
73% With hydrogen In ethanol for 18 h; Preparation III; Synthesis of 4-amino-lH-pyrazole-3-carboxylic acid methyl ester; A mixture of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (12 g, 71 mmol, prepared in an analogous manner to Preparation I) and 10percent Pd/C (1 g) in EtOH (100ml) was stirred under an atmosphere of hydrogen for 18 hours. The mixture was filtered through a plug of Celite, and reduced in vacuo to afford 4-amino-lH- pyrazole-3-carboxylic acid methyl ester as an orange solid (7.2 g, 73percent).

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[18] Patent: WO2007/129062, 2007, A1, . Location in patent: Page/Page column 195
[19] Patent: WO2007/129062, 2007, A1, . Location in patent: Page/Page column 199-200
[20] Patent: US2010/21420, 2010, A1,
[21] Patent: CN107235906, 2017, A, . Location in patent: Paragraph 0094-0097
  • 2
  • [ 67-56-1 ]
  • [ 5334-40-7 ]
  • [ 138786-86-4 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: at 20℃; for 16 h;
Stage #2: With water; sodium hydrogencarbonate In methanol; ethyl acetate		 Reference Example 1
Methyl 4-nitro-1H-pyrazole-3-carboxylate
Acetyl chloride (9 mL) was added dropwise to methanol (90 mL), 4-nitro-1H-pyrazole-3-carboxylic acid (9.00 g, 57.3 mmol) was added to the mixture.
The mixture was stirred at room temperature for 16 hr, and concentrated under reduced pressure.
Methanol was added to the residue, and the mixture was concentrated under reduced pressure, the operation was twice repeated.
The residue was diluted with methanol and ethyl acetate.
5percent sodium hydrogencarbonate aqueous solution was added, and the pH was adjusted to 8-9.
The mixture was extracted with ethyl acetate.
The extract was washed with water, brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (9.83 g, yield 100percent).
1H-NMR (DMSO-d6, 200 MHz): δ 3.98 (3H, s), 8.28 (1H, s).
100%
Stage #2: With sodium hydrogencarbonate In methanol; water; ethyl acetate		 Acetyl chloride (9 mL) was added dropwise to methanol (90 mL), 4-nitro-1H-pyrazole-3-carboxylic acid (9.00 g, 57.3 mmol) was added to the mixture. The mixture was stirred at room temperature for 16 hr, and concentrated under reduced pressure. Methanol was added to the residue, and the mixture was concentrated under reduced pressure, the operation was twice repeated. The residue was diluted with methanol and ethyl acetate. 5percent sodium hydrogencarbonate aqueous solution was added, and the pH was adjusted to 8 - 9. The mixture was extracted with ethyl acetate. The extract was washed with water, brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (9.83 g, yield 100percent). 1H-NMR (DMSO-d6, 200 MHz):δ 3.98(3H, s), 8.28(1H, s).
100% at 20℃; Cooling with ice Dissolve 4-nitro-1H-pyrazole-3-carboxylic acid in methanol (50 ml) and add thionyl chloride (2.5 ml) dropwise on an ice bath. The reaction is allowed to proceed overnight at room temperature. Concentration under reduced pressure gave 4.36 g of a white solid. Yield: 100percent
99.5% at 0 - 22℃; for 48 h; EXAMPLE 1 Synthesis of the methanesulphonic acid salt of 4-{2,6-dichloro-benzoylaminoHH- pyrazole-3-carboxylic acid piperidin-4-ylamide and crystals thereofThe methane sulphonic acid salt of 4-(2,6-dichloro-benzoylamino)-lH-pyrazole-3- carboxylic acid piperidin-4-ylamide may be prepared by the synthetic route shown in the Scheme below. EPO <DP n="73"/>SOCI2, MeOH Stage 1 4H3N3O4 5H5N3O4 Stage 2 C5H7 3O2 FW: 157.09 FW: 171.11 FW: 141.13C12H9CI2N3O3 C11H7CI2N3O3 FW: 314.13 FW: 300.10Stage 5Stage 1 : Preparation of 4-nitro-li7-pyrazole-3-carboxylic acid methyl esterC4H3N3O4 C5H5N3O4 FW: 157.09 FW: 171.11 EPO <DP n="74"/>A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with 4-nitro-l/7-pyrazole-3-carboxylic acid (1.117 Kg, 7.11 mol, 1 wt) and methanol (8.950 L, 8 vol). The reaction mixture was stirred under nitrogen, cooled to 0 to 5 0C, thionyl chloride (0.581 L, 8.0 mol, 0.52 vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22 °C overnight, after which time 1H NMR analysis (d6-DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 45 0C, the residue treated with toluene and re-concentrated (3x 2.250 L, 3x 2vol) under reduced pressure at 40 to 45 0C to give 4-nitro-l/f-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210 Kg, 99.5percent).; EXAMPLE I lPreparation of 4-(2,6-dichloro-benzoylamino)-lH-pyrazole-3-carboxylic acid piperidin-4-ylamide hydrochlorideHA. Synthesis of 4-nitro-lH-pyrazole-3-carboxylic acid methyl esterThionyl chloride (2.90 ml, 39.8 mmol) is slowly added to a mixture of 4-nitro-3- pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in methanol (100 ml) at ambient temperature and the mixture is stirred for 48 hours. The mixture is reduced in EPO <DP n="98"/>vacuo and dried through azeotrope with toluene to afford the 4-nitro-lH-pyrazole- 3-carboxylic acid methyl ester.
99.5% at 0 - 22℃; A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with 4-nitro-1H-pyrazole-3- carboxylic acid (1.117 Kg, 7.11 mol, 1 wt) and methanol (8.950 L, 8 vol). The reaction mixture was stirred under nitrogen, cooled to 0 to 5 °C, thionyl chloride (0.581 L, 8.0 mol, 0.52 vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22 °C overnight, after which time 1H NMR analysis (dβ- DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 45 °C, the residue treated with toluene and re-concentrated (3x 2.250 L, 3x 2vol) under reduced pressure at 40 to 45 °C to give 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210 Kg, 99.5percent).
99.5% at 0 - 22℃; A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with 4-nitro-1H-pyrazole-3- carboxylic acid (1.117 Kg, 7.11 mol, 1 wt) and methanol (8.950 L, 8 vol). The reaction mixture was stirred under nitrogen, cooled to 0 to 5 °C, thionyl chloride (0.581 L, 8.0 mol, 0.52 vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22 °C overnight, after which time 1H NMR analysis (dβ- DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 45 °C, the residue treated with toluene and re-concentrated (3x 2.250 L, 3x 2vol) under reduced pressure at 40 to 45 °C to give 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210 Kg, 99.5percent).
99.5% at 0 - 22℃; A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with 4- nitro-1/-/-pyrazole-3-carboxylic acid (1.117 Kg, 7.11 mol, 1 wt) and methanol (8 950 L, 8 vol). The reaction mixture was stirred under nitrogen, cooled to O to 5 0C, thionyl chloride <n="161"/>(0.581 L1 8.0 mol, 0.52 vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22 0C overnight, after which time 1H NMR analysis (d6-DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 45 0C, the residue treated with toluene and re-concentrated (3x 2.250 L, 3x 2vol) under reduced pressure at 40 to 45 0C to give 4-nitro-1 H-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210 Kg, 99.5percent).
99% at 0 - 70℃; for 5 h; To a solution of 4-nitro-3-pyrazolecarboxylic acid (3.14 g,20.0 mmol) in MeOH (50 mL) was slowly added thionyl chloride(7.3 mL, 0.1 mol) at 0 °C. After the completion of the addition, thetemperature of the reaction mixture increased to 70 °C and stirredfor 5 h. Methanol was removed in vacuo, and the resulting residuewas poured into ice water and extracted with EtOAc. The organiclayer was washed with 10percent NaHCO3 solution, brine and dried overNa2SO4. The resulting reaction mixture concentrated in vacuo toafford 1 as a white solid (3.37 g, 99percent). 1H NMR (400 MHz, DMSO-d6)δ 8.93 (s, 1H), 3.89 (s, 3H); 13C NMR (100 MHz, DMSO-d6)δ 161.4,138.0, 133.7, 132.0, 53.3.
99.8% at 0 - 25℃; for 16 - 24 h; Industry scale Stage 1: Preparation of 4-nitro-lH-pyrazole-3-carboxylic acid methyl esterC4H3N3O4 C5H5N3O4FW: 157.09 FW: 171.114-Nitro-lH-pyrazole-3-carboxylic acid (1.350Kg, 8.59 MoI, 1.0 wt) and methanol (10.80L, 8.0 vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The suspension was cooled to 0 to 5°C under nitrogen and thionyl chloride (0.702L, 9.62 MoI, 0.52 vol) added at this temperature. The mixture was warmed to 15 to 250C over 16 to 24 hours. Reaction completion was determined by 1H NMR analysis (d6-DMSO). The mixture was concentrated under vacuum at 35 to 450C and toluene (2.70L, 2.0 vol) charged to the residue and removed under vacuum at 35 to 45°C. The toluene azeotrope was repeated twice using toluene (2.70L, 2.0 vol) to give 4-nitro-lH-pyrazole-3-carboxylic acid methyl <n="72"/>ester [1.467Kg, 99.8percentth, 108.7percent w/w, 1H NMR Cd6-DMSO) concordant with structure, no entrained solvent] as an off-white solid.
98.3% at 0 - 25℃; for 16 - 24 h; A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with 4-nitro-17f-pyrazole-3-carboxylic acid (1.117Kg, 7.11mol, lwt) and methanol (8.950L5 8vol). The reaction mixture was stirred under nitrogen, cooled to 0 to 50C, thionyl chloride (0.581L, 8.0mol, 0.52vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 220C overnight after which time 1H NMR analysis (d6-DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 450C, the residue treated with toluene and re-concentrated (3x 2.250L, 3x 2vol) under reduced pressure at 40 to 450C to give 4-nitro-l//-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210Kg, 99.5percentth).; 4-Nitro-lH-pyrazole-3-carboxylic acid (1.00kg, 6.37mol, l.Owt) and methanol (8.00L, 8.0vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The suspension was cooled to 0 to 5°C under nitrogen and thionyl chloride (0.52L, 7.12mol, 0.52vol) was added at this temperature. The mixture was warmed to 15 to 25°C over 16 to 24 hours. Reaction completion was determined by 1H NMR analysis (d6-DMSO). The mixture was concentrated under vacuum at 35 to 45°C. Toluene (2.00L, 2.0vol) was charged to the residue and removed under vacuum at 35 to 450C. The azeotrope was repeated twice using toluene (2.00L, 2.0vol) to give 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (1.071Kg, 98.3percent) as an off white solid.
98.3% at 0 - 25℃; for 16 - 48 h; A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with A- nitro-1H-pyrazole-3-carboxylic acid (1.117Kg, 7.11mol, 1wt) and methanol (8.950L, δvol). The reaction mixture was stirred under nitrogen, cooled to 0 to 50C, thionyl chloride (0.581 L, δ.Omol, 0.52vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22°C overnight after which time 1H NMR analysis (d6-DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 450C, the residue treated with toluene and re-concentrated (3x 2.250L, 3x 2vol) under reduced pressure at 40 to 450C to give 4-nitro-1 /-/-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210Kg, 99.5percentth).4-Nitro-1H-pyrazole-3-carboxylic acid (1.00kg, 6.37mol, 1.0wt) and methanol (8.00L, δ.Ovol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The suspension was cooled to 0 to 5°C under nitrogen and thionyl chloride (0.52L, 7.12mol, 0.52vol) was added at this temperature. The mixture was warmed to 15 to 25°C over 16 to 24 hours. Reaction completion was determined by 1H NMR analysis (d6- DMSO). The mixture was concentrated under vacuum at 35 to 45°C. Toluene (2.00L, 2.0vol) was charged to the residue and removed under vacuum at 35 to 450C. The azeotrope was repeated twice using toluene (2.00L, 2.0vol) to give 4-nitro-1 H-pyrazole-3- carboxylic acid methyl ester (1.071 Kg, 98.3percent) as an off white solid.Thionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3- pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in MeOH (100 ml) at ambient temperature and the mixture stirred for 48 hours. The mixture was reduced in vacuo and dried through azeotrope with toluene to afford 4-nitro-1 H-pyrazole-3-carboxylic acid methyl ester as a white solid.1H NMR (400 MHz, DMSO-d6) δ 14.4 (s, 1 H), 8.9 (s, 1 H), 3.9 (s, 3H)4-Nitro-1H-pyrazole-3-carboxylic acid (1.350Kg, 8.59 MoI, 1.0 wt) and methanol (10.80L, 8.0 vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The suspension was cooled to O to 50C under nitrogen and thionyl chloride (0.702L, 9.62 MoI, 0.52 vol) added at this temperature. The mixture was warmed to 15 to 25°C over 16 to 24 hours. Reaction completion was determined by 1H NMR analysis (d6- DMSO). The mixture was concentrated under vacuum at 35 to 45°C and toluene (2.70L, 2.0 vol) charged to the residue and removed under vacuum at 35 to 45°C. The toluene azeotrope was repeated twice using toluene (2.70L, 2.0 vol) to give 4-nitro-1 H-pyrazole-3- carboxylic acid methyl ester [1.467Kg, 99.8percentth, 108.7percent w/w, 1H NMR (d6-DMSO) concordant with structure, no entrained solvent] as an off-white solid.
98.3% at 0 - 25℃; for 16 - 24 h; Stage 4: Synthesis of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester; A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with 4- nitro-lH-pyrazole-3-carboxylic acid (1.117Kg, 7.11mol, lwt) and methanol (8.950L, 8vol). The reaction mixture was stirred under nitrogen, cooled to 0 to 50C, thionyl chloride (0.581L, 8.0mol, 0.52vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22°C overnight after which time 1H NMR analysis (d6-DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 450C, the residue treated with toluene and re-concentrated (3x 2.250L, 3x 2vol) under reduced pressure at 40 to 45°C to give 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210Kg, 99.5percentth).; Stage 4: Preparation of 4-nitro-lH-pyrazole-3-carboxylic acid methyl; esterC4H3N3O4 C5H5N3O4FW: 157.09 FW: 171.114-Nitro-lH-pyrazole-3-carboxylic acid (1.00kg, 6.37mol, l.Owt) and methanol (8.00L, 8.0vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The suspension was cooled to 0 to 5°C under nitrogen and thionyl chloride (0.52L, 7.12mol, 0.52vol) was added at this temperature. The mixture was warmed to 15 to 25°C over 16 to 24 hours. Reaction completion was determined by 1H NMR analysis (dβ-DMSO). The mixture was concentrated under vacuum at 35 to 45°C. Toluene (2.00L, 2.0vol) was charged to the residue and removed under vacuum at 35 to 45°C. The azeotrope was repeated twice using toluene (2.00L, 2.0vol) to give 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (1.071Kg, 98.3percent) as an off white solid.
98% at 20℃; for 24 h; Step 1. Synthesis of methyl 4-nitro-1 /-/-pyrazole-3-carboxylate (C29). Fuming sulfuric acid (4 mL) was added to a solution of 4-nitro-1 /-/-pyrazole-3-carboxylic acid (16.0 g, 102 mmol) in methanol (200 mL), and the reaction was stirred at RT for 24 hours. The reaction mixture was concentrated, and the resulting solid was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, providing C29 as a white solid. Yield: 17.1 g, 99.9 mmol, 98percent. LCMS m/z 170.0 (M-1 ). H NMR (400 MHz, CDCI3) δ 4.05 (s, 3H), 8.40 (s, 1 H).
96.9% at 25℃; for 16 h; 4-nitro-lH-pyrazole-3-carboxylic acid (30.0 g, 191.0 mmol) was dissolved in methanol (300 mL)Sulfoxide (34.1 g, 286.5 mol) was added,25 ° C for 16 hours.The reaction solution was concentrated in vacuo,Saturated sodium bicarbonate solution (400 mL) was added,Ethyl acetate extraction (500 mL x 2),Organic synthesis,Saturated brine (300 mL),Dried over anhydrous sodium sulfate,The product was concentrated in vacuo (31.7 g, 96.9percent yield).
95.8% at 20℃; Example 43trans-5-[3-oxospiro[6-azaisobenzofuran-1(3H),1'-cyclohexan]-4'-yl]-2-phenyl-2,4-dihydroimidazo[4,5-c]pyrazole(1) Preparation of methyl 4-nitro-1H-pyrazole-3-carboxylate Thionyl chloride (5.1 mL, 70.0 mmol) was added portionwise to a solution of 4-nitro-1H-pyrazole-3-carboxylic acid (10.0g, 63.7 mmol) in methanol (100 mL). After the mixture was stirred overnight at room temperature, the solvent was evaporated in vacuo. After the residue was dissolved in ethyl acetate, the solution was washed with water and saturated aqueous brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title compound (10.43 g, 95.8 percent).
92.1% at 25 - 60℃; for 4 h; The 4-nitro-1H-pyrazole-3-carboxylic acid (20.0 g, 0.127 mmol) was dissolved in methanol (100 mL) and thionyl chloride (18.1 g, 0.152 mmol) was added , allowed to react for 2 hours at 25 ° C. , then heated to 60 ° C, and allowed to react for 2 hours. The reaction was concentrated in vacuo and methyl tert-butyl ether (80 mL) was added and filtered to give a white solid which was dried in vacuo to give the product (20.0 g, 92.1percent yield).
91% at 0 - 20℃; for 2 h; Reference Example 18
Methyl 4-nitro-1H-pyrazole-3-carboxylate
To a solution of 4-nitro-1H-pyrazole-3-carboxylic acid (10.0 g, 63.7 mmol) in methanol (100 mL), thionyl chloride (5.1 mL, 70.0 mmol) was added dropwise at 0° C., and the mixture was stirred at room temperature for 2 hr.
The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in ethyl acetate.
This solution was washed with saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous sodium sulfate.
The solvent was evaporated under reduced pressure to give the title compound (9.9 g, yield 91percent).
1H-NMR (CDCl3): δ 4.06 (3H, s), 8.51 (1H, s).
91%
Stage #1: With thionyl chloride In methanol at 20℃; for 2 h;
Stage #2: With sodium hydrogencarbonate In water; ethyl acetate		 To a solution of 4-nitro-1H-pyrazole-3-carboxylic acid (10.0 g, 63.7 mmol) in methanol (100 mL), thionyl chloride (5.1 mL, 70.0 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in ethyl acetate. This solution was washed with saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (9.9 g, yield 91percent). 1H-NMR (CDCl3) :δ 4.06(3H, s), 8.51(1H, s).
91.7% at 20℃; for 16 h; 4-Nitro-1H-pyrazole-3-carboxylic acid (20 g, 127.3 mmol) was dissolved in methanol (200 mL) and thionyl chloride (22.7 g, 190.8 mmol) was added and reacted at 20 ° C for 16 hours. The reaction was completed and concentrated. Methyl tert-butyl ether (200 mL) was added and filtered to give 20 g of the title product in 91.7percent yield.
89% at 65℃; for 16 h; To a solution of 4-nitro-1H-pyrazole-3-carboxylic acid (5 g, 31.8 mmol) in dry MeOH (60 ml) was added freshly crystallized p-toluenesulphonic acid monohydrate (300 mg, 1.6 mmol). The reaction mixture was heated at 65° C. for 16 hrs. MeOH was removed in vacuo. The residue was taken up with saturated aqueous NaHCO3 solution (15 ml) and extracted with EtOAc. The combined organic layers were washed with water, and then with brine, dried (Na2SO4), filtered, and evaporated. The crude product was purified by column chromatography over silica gel using 30percent EtOAc /hexane) to provide the title compound as white solid (4.85 g, 89percent).
89%
Stage #1: at 65℃; for 16 h; Inert atmosphere
Stage #2: With sodium hydrogencarbonate In water		 To a solution of 4-nitro-lH-pyrazole-3-carboxylic acid (5 g, 31.8 mmol) in dry MeOH (60ml) was added freshly crystallized p-toluenesulphonic acid monohydrate (300 mg, 1.6 mmol). The reaction mixture was heated at 65 °C for 16 hrs. MeOH was removed in vacuo. The residue was taken up with saturated aqueous NaHC03 solution (15 ml) and extracted with EtOAc. The combined organic layers were washed with water, and then with brine, dried (Na2S04), filtered, and evaporated. The crude product was purified by column chromatography over silica gel using 30percentEtOAc/hexane) to provide the title compound as white solid (4.85 g, 89percent).
86% for 3.5 h; Heating / reflux Reference Example 1 Methyl 4-nitro-1H-pyrazole-3-carboxylate Conc. sulfuric acid(8.2 mL) was added to 4-nitro-1H-pyrazole-3-carboxylic acid(163.8 g) dissolved in methanol(1.64 L) under argon atmosphere and the mixture was heated under reflux for 3.5 hours. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure and the resulted residue was triturated in diisopropyl ether. The precipitate was collected by filtration to give the titled compound(153.2 g, 86percent yield) as a colorless crystalline. mp.115-117°C, MS(ESI)m/z:170 [M-H]-.
72.7% at 0 - 20℃; for 16 h; Acetyl chloride (6.34 ml, 89 mmol) was added to the mixture of 4-nitro-1H-pyrazole-3-carboxylic acid (2, 7 g, 44.6 mmol) in MeOH (223 ml) at 0 °C.
The mixture was stirred at rt for 16 h.
After concentrated in vacuo, the residue was azeotroped with MeOH two times.
The residue was diluted with MeOH and EtOAc, and the mixture was adjusted to a pH of approx. 9 with satd NaHCO3 aq.
The mixture was extracted with EtOAc.
The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated to give the compound 12 (5.545 g, 32.4 mmol, 72.7percent) as a white powder. 1H NMR (DMSO-d6) δ 14.39 (br s, 1H), 8.99 (s, 1H), 3.89 (s, 3H); 13C NMR (DMSO-d6) δ 161.1, 138.1, 133.2, 130.9, 52.8; HRMS (ESI) m/z: [M−H]− calcd for C5H4N3O4: 170.0207, found: 170.0200.
48.8% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃; for 18 h; A mixture [OF 4-NITRO-LH-PYRAZOLE-3-CARBOXYLIC] acid (2.0 g, 12.7 mmol) in dichloromethane at [25 oC] was treated with 1- (3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (2.68 g, 14.0 mmol), methanol (8.2 mL), and 4- dimethylaminopyridine (155 mg, 1.27 mmol). The reaction was stirred at [25 oC] for 18 h. At this time, the reaction was diluted with dichloromethane and was washed with a 1N aqueous hydrochloric acid solution (1 x 50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 45: 55 ethyl acetate/petroleum ether) afforded 4-nitro- [1H-PYRAZOLE-3-CARBOXYLIC] acid methyl ester (1.06 g, 48.8percent) as a white solid: LR-MS for [C5H5N304] [(M-H) + AT M/Z] = 170.

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[35] Patent: WO2006/3440, 2006, A1, . Location in patent: Page/Page column 154
[36] Patent: WO2007/129062, 2007, A1, . Location in patent: Page/Page column 194-195; 199
[37] Patent: WO2016/144848, 2016, A1, . Location in patent: Page/Page column 36
[38] Patent: WO2016/144846, 2016, A1, . Location in patent: Page/Page column 39; 40
[39] Patent: WO2016/144849, 2016, A1, . Location in patent: Page/Page column 31
[40] Patent: WO2016/144844, 2016, A1, . Location in patent: Page/Page column 32
[41] Patent: WO2016/144847, 2016, A1, . Location in patent: Page/Page column 31
[42] Patent: CN107235906, 2017, A, . Location in patent: Paragraph 0090-0093
[43] Patent: WO2018/64135, 2018, A1, . Location in patent: Paragraph 0454-0457
  • 3
  • [ 5334-40-7 ]
  • [ 138786-86-4 ]
Reference： [1] Patent: US2010/21420, 2010, A1,
[2] Patent: US2010/21420, 2010, A1,
[3] Patent: US2010/55094, 2010, A1,
[4] Patent: US2010/55094, 2010, A1,
  • 4
  • [ 67-56-1 ]
  • [ 7719-09-7 ]
  • [ 5334-40-7 ]
  • [ 138786-86-4 ]
YieldReaction ConditionsOperation in experiment
99.5% at 0 - 25℃; for 16 - 48 h; A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with A- nitro-1 H-pyrazole-3-carboxylic acid (1.117 Kg, 7.1 1 mol, 1 wt) and methanol (8.950 L, 8 vol). The reaction mixture was stirred under nitrogen, cooled to O to 5 0C, thionyl chloride (0.581 L, 8.0 mol, 0.52 vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22 0C overnight, after which time 1H NMR analysis (d6-DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 45 0C, the residue treated with toluene and re-concentrated (3x 2.250 L, 3x 2vol) under reduced pressure at 40 to 45 0C to give 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210 Kg, 99.5percent).; Thionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3- pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in MeOH (100 ml) at ambient temperature and the mixture stirred for 48 hours. The mixture was reduced in vacuo and dried through azeotrope with toluene to afford 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester as a white solid.; Stage 1 : Preparation of 4-nitro-1 H-pvrazole-3-carboxylic acid methyl ester 4-Nitro-1H-pyrazole-3-carboxylic acid (1.350Kg1 8.59 MoI, 1.0 wt) and methanol (10.80L, 8.0 vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The suspension was cooled to O to 5°C under nitrogen and thionyl chloride (0.702L, 9.62 MoI, 0.52 vol) added at this temperature. The mixture was warmed to 15 to 25°C over 16 to 24 hours. Reaction completion was determined by 1H NMR analysis (d6- DMSO). The mixture was concentrated under vacuum at 35 to 45°C and toluene (2.70L, 2.0 vol) charged to the residue and removed under vacuum at 35 to 45°C. The toluene azeotrope was repeated twice using toluene (2.70L, 2.0 vol) to give 4-nitro-1 H-pyrazole-3- carboxylic acid methyl ester [1.467Kg, 99.8percentth, 108.7percent w/w, 1H NMR (d6-DMSO) concordant with structure, no entrained solvent] as an off-white solid.
Reference： [1] Patent: WO2008/9954, 2008, A1, . Location in patent: Page/Page column 83-84; 105
  • 5
  • [ 75-36-5 ]
  • [ 5334-40-7 ]
  • [ 138786-86-4 ]
Reference： [1] Journal of Antibiotics, 2015, vol. 68, # 6, p. 361 - 367
  • 6
  • [ 138786-86-4 ]
  • [ 637336-53-9 ]
Reference： [1] Patent: US2011/306589, 2011, A1,
[2] Patent: WO2003/106459, 2003, A1,
[3] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 10, p. 979 - 984
[4] Patent: CN107235906, 2017, A,
[5] Patent: WO2011/154327, 2011, A1,
[6] Patent: WO2008/51047, 2008, A1,
  • 7
  • [ 138786-86-4 ]
  • [ 74-88-4 ]
  • [ 400877-57-8 ]
YieldReaction ConditionsOperation in experiment
84.1% With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 6.5 h; Cooling with ice Methyl 4-nitro-lH-pyrazole-3-carboxylate (22.10 g, 129.16 mmol)Add 500mL eggplant bottle,Add 200 mL of tetrahydrofuran,60percent NaH (6.72 g, 167.90 mmol) was added portionwise under ice-cooling,After adding ice bath stirring 30min,MeI (12.1 mL, 193.73 mmol) was added dropwise under ice bath,After completion of the reaction at room temperature 6.0h,TLC detection reaction is completed, the reaction solution slowly into ice water,The target product was suction filtered (20.1 g, 84.1percent).
75.2%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil for 0.5 h; Cooling with ice
Stage #2: at 20℃; 		The product obtained in Step 5 (4.36 g) was dissolved in anhydrous tetrahydrofuran (35 ml), sodium hydride (1.22 g, 60percent) was added in portions, and the mixture was ice-cooled for 30 minutes, methyl iodide (2.4 ml) was added dropwise, and the mixture was allowed to react overnight at room temperature. Quenching with water, extraction with ethyl acetate, drying over anhydrous sodium sulfate, suction filtration, concentration under reduced pressure, and flash column chromatography (dichloromethane/methanol = 100:1) gave 3.55 g of a white solid. Yield: 75.2percent.
54%
Stage #1: With potassium carbonate In acetone at 25℃;
Stage #2: at 0 - 70℃; for 2 h; 		To a solution of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (3.1 g, 18.1 mmol) in dry acetone (2 ml) was added K2CO3 (5 g, 36.2 mmol) at 25° C. The reaction mixture was cooled to 0° C., and methyl iodide (2.2 ml, 36.3 mmol) was added. The temperature was again raised to 25° C., and then heated to 70° C. for 2 hrs. The solvent was removed in vacuo The residue was diluted with EtOA and washed with water and with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by column chromatography over silica gel. Elution with 20percent EtOAc /hexane) gave the undesired isomer 2-methyl-4-nitro-2H-pyrazole-3-carboxylic acid methyl ester (1 g, 30percent), subsequent elution with 40percent EtOAc /hexane provided the desired isomer 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.8 g, 54percent).
Reference： [1] Patent: CN107235906, 2017, A, . Location in patent: Paragraph 0126-0129
[2] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 10, p. 979 - 984
[3] Patent: CN107652293, 2018, A, . Location in patent: Paragraph 0102; 0103; 0104
[4] Patent: US2011/306589, 2011, A1, . Location in patent: Page/Page column 53
[5] Patent: WO2016/144846, 2016, A1, . Location in patent: Page/Page column 40
[6] Patent: WO2016/144849, 2016, A1, . Location in patent: Page/Page column 31
[7] Patent: WO2016/144844, 2016, A1, . Location in patent: Page/Page column 33-34
[8] Patent: WO2016/144847, 2016, A1, . Location in patent: Page/Page column 31; 32
  • 8
  • [ 138786-86-4 ]
  • [ 400877-57-8 ]
YieldReaction ConditionsOperation in experiment
82.8%
Stage #1: With sodium nitrite In tetrahydrofuran at 0℃; for 1 h;
Stage #2: With methyl iodide In tetrahydrofuran at 25℃; for 18 h; 		A mixture of sodium hydride (167 mg, 6. [96] mmol) in tetrahydrofuran (15 mL) cooled to [0 oC] was treated with a solution [OF 4-NITRO-LH-PYRAZOLE-3-CARBOXYLIC] acid methyl ester (1.0 g, 5.8 mmol) in tetrahydrofuran (10 mL). This mixture was stirred at [0 oC] for 1 h. It was then treated with methyl iodide (0.54 mL, 8.7 mmol). The reaction was stirred at [25 oC] for 18 h. At this time, the reaction was cooled to 0 oC and was then quenched with a saturated aqueous ammonium chloride solution and diluted with ethyl acetate (200 mL). This solution was washed with water (1 x 100 mL) and a saturated aqueous sodium chloride solution (1 x 100 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was slurried in 40percent ethyl acetate/petroleum ether and cooled in the freezer for 15 min. At this time, the solids were collected by filtration to afford [L-METHYL-4-NITRO-LH-] pyrazole-3-carboxylic acid methyl ester (889 mg, 82.8percent) as a white solid
Reference： [1] Patent: WO2003/106459, 2003, A1, . Location in patent: Page 162
  • 9
  • [ 138786-86-4 ]
  • [ 74-88-4 ]
  • [ 400877-57-8 ]
  • [ 309740-49-6 ]
YieldReaction ConditionsOperation in experiment
33% With potassium carbonate In acetone at 70℃; for 2 h; Compound 6 and 6A: To a mixture containing 5 (3.1 g, 18.1 mmol) and potassium carbonate (5.0 g, 36.2 mmol) in 60 mL of acetone was added methyl iodide (2.2 mL, 36.2 mmol). The resulting solution was heated and stirred at 70° C. for 2 hours. After the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate (.x.3). The combined organics were washed with brine, dried (MgSO4), and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using 20percent ethyl acetate in hexanes as the eluent to afford 6 (1.1 g, 33percent) as white solid. 1H NMR (d6-DMSO) δ 3.96 (s, 3H) 3.98 (s, 3H) 8.36 (s, 1H); ES (+) MS m/e=186 (M+1) and using 30percent ethyl acetate in hexanes to afford 6A (2.2 g, 66percent) as white solid. 1H NMR (d-CDCl3) δ 3.98 (s, 3H) 4.00 (s, 3H) 8.13 (s, 1H); ES (+) MS m/e=186 (M+1).
Reference： [1] Patent: US2007/27166, 2007, A1, . Location in patent: Page/Page column 79
[2] Patent: EP1956009, 2008, A1, . Location in patent: Page/Page column 40
[3] Patent: EP1970373, 2008, A1, . Location in patent: Page/Page column 91
  • 10
  • [ 138786-86-4 ]
  • [ 74-88-4 ]
  • [ 400877-57-8 ]
  • [ 309740-49-6 ]
YieldReaction ConditionsOperation in experiment
54% With potassium carbonate In acetone at 0 - 70℃; Inert atmosphere To a solution of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (3.1 g, 18.1 mmol) in dry acetone (2 ml) was added K2C03 (5 g, 36.2 mmol) at 25°C. The reaction mixture was cooled to 0°C, and methyl iodide (2.2 ml, 36.3 mmol) was added. The temperature was again raised to 25°C, and then heated to 70°C for 2 hrs. The solvent was removed in vacuo The residue was diluted with EtOA and washed with water and with brine, dried (Na2S04), filtered, and concentrated. The crude product was purified by column chromatography over silica gel. Elution with 20percent EtOAc/hexane) gave the undesired isomer 2-methyl-4-nitro-2H-pyrazole-3-carboxylic acid methyl ester (1 g, 30percent), subsequent elution with 40percent EtOAc/hexane provided the desired isomer l-methyl-4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (1.8 g, 54percent).
53% With caesium carbonate In N,N-dimethyl-formamideInert atmosphere Preparative Example 7
4-nitro-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester
340 mg (1.99 mM) of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester was dissolved in 4 ml of N,N-dimethylformamide, to which 0.33 ml (2.19 mM) of iodomethane and 1.3 g (3.98 mM) of cesium carbonate were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes.
The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine.
The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure.
The resulting impure compound was purified by column chromatography (hexane:ethyl acetate=2:1), to obtain 195 mg (53percent) of the title compound and 110 mg (30percent) of the compound of Preparative Example 13.
1H NMR (300 MHz, CDCl3) δ 4.00 (s, 3H), 4.02 (s, 3H), 8.15 (s, 1H).
Mass: 185 (M+)
; 340 mg (1.99 mM) of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester was dissolved in 4 ml of N,N-dimethylformamide, to which 0.33 ml (2.19 mM) of iodomethane and 1.3 g (3.98 mM) of cesium carbonate were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane:ethyl acetate=2:1), to obtain 110 mg (30percent) of the title compound and 195 mg (53percent) of the compound of Preparative Example 7.1H NMR (300 MHz, CDCl3) δ 4.03 (s, 3H), 4.04 (s, 3H), 8.03 (s, 1H).
53% With caesium carbonate In N,N-dimethyl-formamide for 0.5 h; 340 mg (1.99 mM) of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester was dissolved in 4 ml of N,N-dimethylformamide, to which 0.33 ml (2.19 mM) of iodomethane and 1.3 g (3.98 mM) of cesium carbonate were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane : ethyl acetate = 2 : 1), to obtain 195 mg (53percent) of the title compound and 110 mg (30percent) of the compound of Preparative Example 13. 1H νMR(300MHz, CDCl3) δ 4.00(s, 3H), 4.02(s, 3H), 8.15(s, IH).Mass : 185(M+); 340 mg (1.99 mM) of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester was dissolved in 4 ml of N,N-dimethylformamide, to which 0.33 ml (2.19 mM) of iodomethane and 1.3 g (3.98 mM) of cesium carbonate were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. The solvent was distilled off under reduced EPO <DP n="31"/>pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane : ethyl acetate = 2 : 1), to obtain 110 mg (30percent) of the title compound and 195 mg (53percent) of the compound of Preparative Example 7.1H NMR(SOOMHZ, CDCl3) δ 4.03(s, 3H), 4.04(s, 3H), 8.03(s, IH).
28% With potassium carbonate In acetone at 30℃; for 5 h; Reference Example 20
Methyl 1-methyl-4-nitro-1H-pyrazole-5-carboxylate
A mixture of methyl 4-nitro-1H-pyrazole-3-carboxylate obtained in Reference Example 18 (2.0 g, 11.7 mmol), methyl iodide (2.0 g, 14.0 mmol), potassium carbonate (1.62 g, 11.7 mmol) and acetone (60 mL) was stirred at 30° C. for 5 hr.
The mixture was diluted with water, and extracted with chloroform.
The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4:1-1:1) to give the title compound, methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate (Rf value 0.43) (0.95 g, yield 44percent) and the title compound, methyl 1-methyl-4-nitro-1H-pyrazole-5-carboxylate (Rf value 0.71) (0.61 g, yield 28percent).
44% With potassium carbonate In acetone at 30℃; for 5 h; A mixture of methyl 4-nitro-1H-pyrazole-3-carboxylate obtained in Reference Example 18 (2.0 g, 11.7 mmol), methyl iodide (2.0 g, 14.0 mmol), potassium carbonate (1.62 g, 11.7 mmol) and acetone (60 mL) was stirred at 30°C for 5 hr. The mixture was diluted with water, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4:1 - 1:1) to give the title compound, methyl 1-methyl-4-nitro-1-pyrazole-3-carboxylate (Rf value 0.43) (0.95 g, yield 44percent) and the title compound, methyl 1-methyl-4-nitro-1H-pyrazole-5-carboxylate (Rf value 0.71) (0.61 g, yield 28percent). Methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate 1H-NMR (CDCl3):δ 3.99(3H, s), 4.01(3H, s), 8.13(1H, s). Methyl 1-methyl-4-nitro-1H-pyrazole-5-carboxylate 1H-NMR (CDCl3):δ 4.02(3H, s), 4.03(3H, s), 8.01 (1H, s).

Reference： [1] Patent: WO2011/154327, 2011, A1, . Location in patent: Page/Page column 136; 137
[2] Patent: US2010/63106, 2010, A1, . Location in patent: Page/Page column 11;13
[3] Patent: WO2008/51047, 2008, A1, . Location in patent: Page/Page column 25; 28-29
[4] Patent: US2009/156582, 2009, A1, . Location in patent: Page/Page column 30
[5] Patent: EP1847531, 2007, A1, . Location in patent: Page/Page column 43
  • 11
  • [ 67-56-1 ]
  • [ 138786-86-4 ]
  • [ 400877-57-8 ]
  • [ 309740-49-6 ]
YieldReaction ConditionsOperation in experiment
31% With cyanomethylenetributyl-phosphorane In toluene at 110℃; for 0.5 h; Sealed tube; Microwave irradiation General procedure: The reaction was performed in 2 batches. In a sealed tube, cyanomethylenetributyl phosphorane (9.28 mL, 35.40 mmol) was added to a solution of 3-methyl-5-nitro-lH- pyrazole (1.50 g, 1 1.80 mmol) and 3-hydroxymethyl-3-methyloxethane (3.53 mL, 35.40 mmol) in toluene (100 mL). The solution was heated at 60 °C for 18 h. The 2 batches were combined and the solvent was evaporated in vacuo. The residue (black oil) was purified by column chromatography on silica gel (irregular SiOH, 15-40 μιη, 330 g, liquid loading on DCM, mobile phase: heptane/EtOAc, gradient from 90: 10 to 50:50). The fractions containing the product were combined and evaporated to dryness to give 3.95 g of intermediate 303 (79percent yield, orange oil) directly used as it in the next step.
Reference： [1] Patent: WO2018/2217, 2018, A1, . Location in patent: Page/Page column 299; 306
  • 12
  • [ 138786-86-4 ]
  • [ 74-88-4 ]
  • [ 400877-57-8 ]
Reference： [1] Patent: US2004/14766, 2004, A1,
  • 13
  • [ 138786-86-4 ]
  • [ 74-88-4 ]
  • [ 400877-57-8 ]
  • [ 309740-49-6 ]
YieldReaction ConditionsOperation in experiment
33% With potassium carbonate In acetone at 70℃; for 2 h; Compound 6 and 6A: To a mixture containing 5 (3.1 g, 18.1 mmol) and potassium carbonate (5.0 g, 36.2 mmol) in 60 mL of acetone was added methyl iodide (2.2 mL, 36.2 mmol). The resulting solution was heated and stirred at 70° C. for 2 hours. After the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate (.x.3). The combined organics were washed with brine, dried (MgSO4), and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using 20percent ethyl acetate in hexanes as the eluent to afford 6 (1.1 g, 33percent) as white solid. 1H NMR (d6-DMSO) δ 3.96 (s, 3H) 3.98 (s, 3H) 8.36 (s, 1H); ES (+) MS m/e=186 (M+1) and using 30percent ethyl acetate in hexanes to afford 6A (2.2 g, 66percent) as white solid. 1H NMR (d-CDCl3) δ 3.98 (s, 3H) 4.00 (s, 3H) 8.13 (s, 1H); ES (+) MS m/e=186 (M+1).
Reference： [1] Patent: US2007/27166, 2007, A1, . Location in patent: Page/Page column 79
[2] Patent: EP1956009, 2008, A1, . Location in patent: Page/Page column 40
[3] Patent: EP1970373, 2008, A1, . Location in patent: Page/Page column 91
  • 14
  • [ 67-56-1 ]
  • [ 138786-86-4 ]
  • [ 309740-49-6 ]
YieldReaction ConditionsOperation in experiment
61% With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In toluene at 20℃; To a solution of 14 (5 g, 29.2 mmol), methanol (5.93 mL, 146mmol) and tributylphosphine (14.6 mL, 58.4 mmol) in toluene(500 mL) was added 1,10-(azodicarbonyl)dipiperidine (14.8 g,58.4 mmol) at room temperature. The mixture was stirred at roomtemperature overnight. The insoluble material was removed by filtration,and the filtrate was partitioned between EtOAc and water.The organic layer was separated, washed with aqueous saturatedNaHCO3 and brine, dried over Na2SO4, filtered, and concentratedin vacuo. The residue was purified by column chromatography (silicagel, 30 g, eluted with 0–70percent EtOAc in hexane) to give 15b (3.28g, 61percent yield) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) d 4.03(3H, s), 4.03 (3H, s), 8.02 (1H, s).
Reference： [1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 9, p. 2452 - 2465
  • 15
  • [ 138786-86-4 ]
  • [ 74-88-4 ]
  • [ 309740-49-6 ]
YieldReaction ConditionsOperation in experiment
34.5% With potassium carbonate In acetone at 50℃; for 4 h; 4-Nitro-lH-pyrazole-3-carboxylic acid methyl ester (3.4 g, 19.9 mmol) was dissolved in acetone (50 mL)Methyl iodide (5.7 g, 40.22 mmol) and potassium carbonate (5.5 g, 39.9 mmol)Heated to 50 ° C,Reaction for 4 hours.Cooled to room temperature,filter,The filtrate was concentrated in vacuo,The residue was purified by silica gel column chromatography (petroleum ether: 1: ethyl acetate = 2) to give the product(1.27 g, yield: 34.5percent).
Reference： [1] Patent: CN107226807, 2017, A, . Location in patent: Paragraph 0274-0276
  • 16
  • [ 138786-86-4 ]
  • [ 74-88-4 ]
  • [ 400877-57-8 ]
  • [ 309740-49-6 ]
YieldReaction ConditionsOperation in experiment
54% With potassium carbonate In acetone at 0 - 70℃; Inert atmosphere To a solution of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (3.1 g, 18.1 mmol) in dry acetone (2 ml) was added K2C03 (5 g, 36.2 mmol) at 25°C. The reaction mixture was cooled to 0°C, and methyl iodide (2.2 ml, 36.3 mmol) was added. The temperature was again raised to 25°C, and then heated to 70°C for 2 hrs. The solvent was removed in vacuo The residue was diluted with EtOA and washed with water and with brine, dried (Na2S04), filtered, and concentrated. The crude product was purified by column chromatography over silica gel. Elution with 20percent EtOAc/hexane) gave the undesired isomer 2-methyl-4-nitro-2H-pyrazole-3-carboxylic acid methyl ester (1 g, 30percent), subsequent elution with 40percent EtOAc/hexane provided the desired isomer l-methyl-4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (1.8 g, 54percent).
53% With caesium carbonate In N,N-dimethyl-formamideInert atmosphere Preparative Example 7
4-nitro-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester
340 mg (1.99 mM) of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester was dissolved in 4 ml of N,N-dimethylformamide, to which 0.33 ml (2.19 mM) of iodomethane and 1.3 g (3.98 mM) of cesium carbonate were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes.
The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine.
The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure.
The resulting impure compound was purified by column chromatography (hexane:ethyl acetate=2:1), to obtain 195 mg (53percent) of the title compound and 110 mg (30percent) of the compound of Preparative Example 13.
1H NMR (300 MHz, CDCl3) δ 4.00 (s, 3H), 4.02 (s, 3H), 8.15 (s, 1H).
Mass: 185 (M+)
; 340 mg (1.99 mM) of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester was dissolved in 4 ml of N,N-dimethylformamide, to which 0.33 ml (2.19 mM) of iodomethane and 1.3 g (3.98 mM) of cesium carbonate were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane:ethyl acetate=2:1), to obtain 110 mg (30percent) of the title compound and 195 mg (53percent) of the compound of Preparative Example 7.1H NMR (300 MHz, CDCl3) δ 4.03 (s, 3H), 4.04 (s, 3H), 8.03 (s, 1H).
53% With caesium carbonate In N,N-dimethyl-formamide for 0.5 h; 340 mg (1.99 mM) of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester was dissolved in 4 ml of N,N-dimethylformamide, to which 0.33 ml (2.19 mM) of iodomethane and 1.3 g (3.98 mM) of cesium carbonate were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane : ethyl acetate = 2 : 1), to obtain 195 mg (53percent) of the title compound and 110 mg (30percent) of the compound of Preparative Example 13. 1H νMR(300MHz, CDCl3) δ 4.00(s, 3H), 4.02(s, 3H), 8.15(s, IH).Mass : 185(M+); 340 mg (1.99 mM) of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester was dissolved in 4 ml of N,N-dimethylformamide, to which 0.33 ml (2.19 mM) of iodomethane and 1.3 g (3.98 mM) of cesium carbonate were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. The solvent was distilled off under reduced EPO <DP n="31"/>pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane : ethyl acetate = 2 : 1), to obtain 110 mg (30percent) of the title compound and 195 mg (53percent) of the compound of Preparative Example 7.1H NMR(SOOMHZ, CDCl3) δ 4.03(s, 3H), 4.04(s, 3H), 8.03(s, IH).
28% With potassium carbonate In acetone at 30℃; for 5 h; Reference Example 20
Methyl 1-methyl-4-nitro-1H-pyrazole-5-carboxylate
A mixture of methyl 4-nitro-1H-pyrazole-3-carboxylate obtained in Reference Example 18 (2.0 g, 11.7 mmol), methyl iodide (2.0 g, 14.0 mmol), potassium carbonate (1.62 g, 11.7 mmol) and acetone (60 mL) was stirred at 30° C. for 5 hr.
The mixture was diluted with water, and extracted with chloroform.
The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4:1-1:1) to give the title compound, methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate (Rf value 0.43) (0.95 g, yield 44percent) and the title compound, methyl 1-methyl-4-nitro-1H-pyrazole-5-carboxylate (Rf value 0.71) (0.61 g, yield 28percent).
44% With potassium carbonate In acetone at 30℃; for 5 h; A mixture of methyl 4-nitro-1H-pyrazole-3-carboxylate obtained in Reference Example 18 (2.0 g, 11.7 mmol), methyl iodide (2.0 g, 14.0 mmol), potassium carbonate (1.62 g, 11.7 mmol) and acetone (60 mL) was stirred at 30°C for 5 hr. The mixture was diluted with water, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4:1 - 1:1) to give the title compound, methyl 1-methyl-4-nitro-1-pyrazole-3-carboxylate (Rf value 0.43) (0.95 g, yield 44percent) and the title compound, methyl 1-methyl-4-nitro-1H-pyrazole-5-carboxylate (Rf value 0.71) (0.61 g, yield 28percent). Methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate 1H-NMR (CDCl3):δ 3.99(3H, s), 4.01(3H, s), 8.13(1H, s). Methyl 1-methyl-4-nitro-1H-pyrazole-5-carboxylate 1H-NMR (CDCl3):δ 4.02(3H, s), 4.03(3H, s), 8.01 (1H, s).

Reference： [1] Patent: WO2011/154327, 2011, A1, . Location in patent: Page/Page column 136; 137
[2] Patent: US2010/63106, 2010, A1, . Location in patent: Page/Page column 11;13
[3] Patent: WO2008/51047, 2008, A1, . Location in patent: Page/Page column 25; 28-29
[4] Patent: US2009/156582, 2009, A1, . Location in patent: Page/Page column 30
[5] Patent: EP1847531, 2007, A1, . Location in patent: Page/Page column 43
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YieldReaction ConditionsOperation in experiment
31% With cyanomethylenetributyl-phosphorane In toluene at 110℃; for 0.5 h; Sealed tube; Microwave irradiation General procedure: The reaction was performed in 2 batches. In a sealed tube, cyanomethylenetributyl phosphorane (9.28 mL, 35.40 mmol) was added to a solution of 3-methyl-5-nitro-lH- pyrazole (1.50 g, 1 1.80 mmol) and 3-hydroxymethyl-3-methyloxethane (3.53 mL, 35.40 mmol) in toluene (100 mL). The solution was heated at 60 °C for 18 h. The 2 batches were combined and the solvent was evaporated in vacuo. The residue (black oil) was purified by column chromatography on silica gel (irregular SiOH, 15-40 μιη, 330 g, liquid loading on DCM, mobile phase: heptane/EtOAc, gradient from 90: 10 to 50:50). The fractions containing the product were combined and evaporated to dryness to give 3.95 g of intermediate 303 (79percent yield, orange oil) directly used as it in the next step.
Reference： [1] Patent: WO2018/2217, 2018, A1, . Location in patent: Page/Page column 299; 306
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Reference： [1] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 10, p. 979 - 984

Tags: 138786-86-4 synthesis path| 138786-86-4 SDS| 138786-86-4 COA| 138786-86-4 purity| 138786-86-4 application| 138786-86-4 NMR| 138786-86-4 COA| 138786-86-4 structure

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